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Trial watch: beta-blockers in cancer therapy

OncoImmunology

November 2023
12(1)

DOI:10.1080/2162402X.2023.2284486

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Authors:

Killian Carnet Le Provost

Oliver Kepp

Institut de Cancérologie Gustave Roussy

Lucillia Bezu

Institut de Cancérologie Gustave Roussy

Compelling evidence supports the hypothesis that stress negatively impacts cancer development and prognosis. Irrespective of its physical, biological or psychological source, stress triggers a physiological response that is mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic adrenal medullary axis. The resulting release of glucocorticoids and catecholamines into the systemic circulation leads to neuroendocrine and metabolic adaptations that can affect immune homeostasis and immunosurveillance, thus impairing the detection and eradication of malignant cells. Moreover, catecholamines directly act on β-adrenoreceptors present on tumor cells, thereby stimulating survival, proliferation, and migration of nascent neoplasms. Numerous preclinical studies have shown that blocking adrenergic receptors slows tumor growth, suggesting potential clinical benefits of using β-blockers in cancer therapy. Much of these positive effects of β-blockade are mediated by improved immunosurveillance. The present trial watch summarizes current knowledge from preclinical and clinical studies investigating the anticancer effects of β-blockers either as standalone agents or in combination with conventional antineoplastic treatments or immunotherapy.

Chemical structures of the most employed cardioselective β-blockers (a) and non-selective β-blockers (b). Red = aryloxypropanolamine and green = phenylethanolamine β-blockers.

…

Scheme of the biological effects of β-blockers.

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Trial watch: beta-blockers in cancer therapy

Killian Carnet Le Provost

a,b

, Oliver Kepp

a,b

, Guido Kroemer

a,b,c

, and Lucillia Bezu

a,b,d

Equipe Labellisée Par La Ligue Contre Le Cancer, Université de Paris, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers,

Institut Universitaire de France, Paris, France;

Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Université Paris Saclay,

Villejuif, France;

Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France;

Gustave Roussy, Département d’anesthésie, Chirurgie

et Interventionnel, Villejuif, France

ABSTRACT

Compelling evidence supports the hypothesis that stress negatively impacts cancer development and

prognosis. Irrespective of its physical, biological or psychological source, stress triggers a physiological

response that is mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic adrenal

medullary axis. The resulting release of glucocorticoids and catecholamines into the systemic circulation

leads to neuroendocrine and metabolic adaptations that can aect immune homeostasis and immuno-

surveillance, thus impairing the detection and eradication of malignant cells. Moreover, catecholamines

directly act on β-adrenoreceptors present on tumor cells, thereby stimulating survival, proliferation, and

migration of nascent neoplasms. Numerous preclinical studies have shown that blocking adrenergic

receptors slows tumor growth, suggesting potential clinical benets of using β-blockers in cancer therapy.

Much of these positive eects of β-blockade are mediated by improved immunosurveillance. The present

trial watch summarizes current knowledge from preclinical and clinical studies investigating the antic-

ancer eects of β-blockers either as standalone agents or in combination with conventional antineoplastic

treatments or immunotherapy.

ARTICLE HISTORY

Received 6 September 2023

Revised 11 November 2023

Accepted 13 November 2023

KEYWORDS

Beta-adrenoreceptors;

beta-blockers; cancer;

catecholamines; stress

Introduction

Stress typically leads to the co-activation of the hypothalamic-

pituitary-adrenal (HPA) axis and the sympathetic adrenal

medullary (SAM) axis, resulting in the systemic elevation of

stress hormones, namely glucocorticoids produced by the adre-

nal cortex and catecholamines (including epinephrine and

norepinephrine) that are released from the adrenal medulla

into the circulation.

1,2

Catecholamines act on adrenergic recep-

tors (ARs), thus increasing heart rate and blood pressure to

prepare the organism for a fight-or-flight response.

ARs

belong to the G-protein-coupled receptor super-family and

are categorized into α- and β-ARs based on their location and

function. α-ARs are divided into two classes: α1-AR, predomi-

nantly found on blood vessels, which increase blood pressure

upon activation, and α2-AR, mainly located within solid

organs such as the pancreas, where they control insulin synth-

esis. β-receptors can be further classified into three types:

β1-AR (found in the heart, blood vessels, kidney, and ciliary

muscle), β2-AR (located in the lungs and ciliary muscle), and

β3-AR (present only in smooth muscle tissue). β-ARs play

a major role in stimulating cardiovascular functions and pro-

moting the relaxation of the smooth muscles in bronchi and

blood vessels. Table 1

β-blockers are specific antagonists targeting β-ARs. The first

synthetic molecules dichloroisoprenaline and pronethalol were

derived from epinephrine in the late 1950s, but were with-

drawn from clinical use several years later due to severe

cardiotoxic side effects.

However, in 1962, propranolol,

a non-cardioselective agent that targets both β1 and β2 recep-

tors, was found to promote negative chronotropic, bathmotro-

pic, inotropic, and dromotropic cardiac effects and a decrease

in kidney renin production (resulting in decreased blood pres-

sure), thus providing safe clinical use.

Subsequently, cardio-

selective agents including acebutolol, atenolol, bisoprolol, and

nebivolol were introduced. These agents specifically target

β1-ARs, thus limiting side effects such as vaso- and broncho-

constriction. Currently, β-blockers are broadly used in clinical

practice, primarily for regulating dysrhythmia, and arterial

hypertension, preventing heart attacks and migraines, as well

as for treating glaucoma. However, misuse of these agents can

cause severe hypotension, bradycardia, asthenia, asthma or

Raynaud’s syndrome, and contraindications, such as cardiac

conduction disturbances or chronic obstructive pulmonary

disease have to be respected. Table 1

β-blockers can be subdivided into two pharmacological

classes: phenylethanolamines and aryloxypropanolamines.

Phenylethanolamines are composed of an aromatic group

linked to an ethylamine substituted by a hydroxyl on position

1. β -blockers of this class such as sotalol or labetalol are non-

cardioselective and act on-target on β1 receptors while often

causing off-target β2 receptor-mediated side effects.

Compounds from the group of aryloxypropanolamines includ-

ing carvedilol, nebivolol and propafenone possess an aromatic

group linked to a propylamine substituted by a hydroxyl on

CONTACT Guido Kroemer kroemer@orange.fr; Lucillia Bezu lucilliabe@gmail.com Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre

le cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France

ONCOIMMUNOLOGY

2023, VOL. 12, NO. 1, 2284486

https://doi.org/10.1080/2162402X.2023.2284486

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a

repository by the author(s) or with their consent.

Table 1. Adrenergic receptors and their main agonists and antagonists in clinic use (non-exhaustive list).

Receptors Endogenous agonists aﬃnity

Pharmacological

agonists Agonist properties

Pharmacological

antagonists

α1 Epinephrine < norepinephrine Epinephrine, norepinephrine,

phenylephrine

Smooth muscle constriction in viscera, skin, sphincter, mucosa, vessels, iris mydriasis Alfuzosin, hydroxyzine, tamsulosin

α2 Epinephrine = norepinephrine Clonidine, dexmedetomidine,

epinephrine,

norepinephrine

Smooth muscle constriction, decreased insulin and glucagon production, decreased thyroid

hormone production, decrease platelet aggregation

Diverse antipsychotics

β1 Epinephrine Dobutamine, epinephrine,

isoprenaline

Chronotropic, dromotropic, inotropic, bathmotropic eﬀects, increased renin production Atenolol, bisoprolol, metoprolol, nebivolol,

propranolol, timolol

β2 Epinephrine > norepinephrine Epinephrine, isoprenaline,

salbutamol, terbutaline

Smooth muscle relaxation, vessels dilatation, enhanced lipolysis, bronchodilatation Propranolol, timolol

β3 Epinephrine = norepinephrine Amibegron, mirabegron,

solabegron

Enhanced lipolysis smooth muscle relaxation of bladder and bowel SR 59230A

2K. CARNET LE PROVOST ET AL.

position 2 and have an additional methyl group on the amine

chain, which increases their activity and selectivity. Of note, the

size of the aromatic group of a β-blocker determines its ability

to activate adrenergic receptors. Thus, a small aromatic group

as the one of epinephrine allows activation of adrenergic recep-

tors, whereas a voluminous group such as the one of pronetha-

lol induces an antagonistic effect. Moreover, a β-blocker

becomes cardioselective if its activity on β1 receptors is higher

than that on β2 receptors. Agonistic activity on β1 receptor

allows vasodilatation that decreases blood pressure, while acti-

vating β2 promotes side effects such as bronchoconstriction.

This selectivity is due to a hydrogen group inducing

a preferential interaction with the β1 receptor.

Cardioselective β-blockers include acebutolol, atenolol, biso-

prolol, and nebivolol, while the most employed non-cardiose-

lective β-blockers are propranolol, sotalol and timolol.

(Figure 1)

Surgical removal of the primary tumor plays a crucial role in

improving the overall survival of cancer patients. However, the

physical excision of the tumor by the surgeon can release

circulating tumor cells, which can spread micrometastases to

distant organs. Additionally, surgical procedures can cause

stress such as pain, nociception, inflammation, and tissue

damage, which in turn trigger a cascade of local and systemic

signaling pathways, activating corticotropic signaling. This

results in the secretion of adrenocorticotropic hormone

(ACTH), catecholamines, and cortisol, proportional to the

stress caused during surgery, leading to critical neuroendocrine

and metabolic changes known as ‘glucocorticoid stress’.

6,7

Moreover, stress hormones released into the systemic circula-

tion can negatively impact both humoral and cellular

immunity.

8,9

Thus, ACTH inhibits the synthesis of immuno-

globulins by plasma cells, while catecholamines can act on

adrenoceptors expressed on natural killer (NK) cells, periph-

eral mononuclear cells and CD4

T lymphocytes,

trigger-

ing the production of intracellular cyclic adenosine

monophosphate (cAMP) and protein kinase A (PKA), alto-

gether abrogating chemotaxis, migration and cytotoxic

functions.

11–13

Moreover, glucocorticoid stress can impact

type I interferon (IFN) production by dendritic cells, as well

as the release of IFN- γ by cytotoxic T lymphocytes (CTLs),

thus broadly compromising adaptive antitumor immune

responses.

14,15

Studies in a rat mammary adenocarcinoma

model also showed that injection of catecholamines inhibited

NK cell-mediated tumor lysis and suppressed resistance to NK-

sensitive metastasis.

Furthermore, endogenous stress hor-

mones have been shown to activate β2-ARs and downstream

cAMP-PKA signaling pathways that increased the activity of

matrix metalloproteinases (MMP), further promoting the dis-

semination of malignant cells. They were also shown to stimu-

late STAT3 signaling in cells surrounding the tumor tissue,

leading to the release of pro-inflammatory cytokines, including

IL-6 and IL-8, and an increase in the secretion of vascular

endothelial growth factor (VEGF), thus promoting tumor

growth and neovascularization, respectively.

17–20

In a murine

model of pancreatic cancer, chronic stress increased levels of

circulating steroids and adrenal tyrosine resulting in impaired

immune responses, with a decreased response of ex vivo sple-

nocytes to lipopolysaccharide, a decrease in cytotoxic

T-lymphocyte-associated protein 4 (CTLA-4) expression in

CD4

cells, and an increase in regulatory T cells in the tumor

bed, altogether stimulating tumor growth and impacting on

overall survival.

In yet another study using a murine model of

MDA-MB-231 breast cancer, stress-induced epinephrine pro-

duction was found to promote tumor growth in a time- and

concentration-dependent manner.

Additionally, in an obser-

vational retrospective trial, Cox regression analysis revealed

low serum epinephrine as a predictor of positive prognosis.

Thus, breast cancer patients with low serum epinephrine levels

had a significantly better overall (OS) and disease-free survival

(DFS) compared to patients with high epinephrine levels.

Surprisingly, colon cancer cells are also able to produce immu-

noregulatory glucocorticoids to suppress the activation of

immune cells. Finally, many data support that both endogen-

ous as well as exogenous corticoids might diminish therapies-

induced anti-tumor response. In summary, while oncological

interventions are crucial for achieving remission in clinical

routine, they paradoxically decrease the immunosurveillance

necessary to avoid immune escape thus promoting the devel-

opment of secondary lesions due to ‘glucocorticoid

stress’.

14,23,24

Figure 1. Chemical structures of the most employed cardioselective β-blockers (a) and non-selective β-blockers (b). Red = aryloxypropanolamine and

green = phenylethanolamine β-blockers.

ONCOIMMUNOLOGY 3

Psychosocial stress has been suggested as a putative cause of

cancer incidence and mortality for a long time, however, deter-

mining a cause–effect relationship has been challenging and was

not firmly established.

The influence of persistent corticotropic

signaling on major antitumor immunological effectors, such as

NK cells, dendritic cells (DC), and T-lymphocytes, has been

explored through various approaches.

T lymphocytes obtained

from the serum of stressed individuals exhibited a shift in pheno-

type from Th1 to Th2, potentially affecting immune signaling

pathways.

Moreover, in both animal models and human studies,

psychosocial stress was found to negatively impact NK cell activity

and promote tumor growth. In a murine colon carcinoma model,

social isolation stress decreased splenic NK cell activity while

increasing angiogenesis leading to the formation of secondary

tumors.

28,29

Conversely, NK cells from ovarian cancer patients

became more efficient at lysing tumor cells after receiving psy-

chosocial support during the perioperative period.

Furthermore,

preclinical data suggest that psychosocial stress activates β-adre-

nergic signaling and promotes tumor progression. Thus, in

a murine hepatocellular carcinoma model, restraint stress pro-

moted tumor growth and increased norepinephrine levels

through β-adrenergic signaling.

In an orthotopic ovarian carci-

noma model, mice subjected to restraint stress experienced

increased tumor growth and VEGF-mediated vascularization,

which correlated with the level of circulating stress hormones.

However, premedication with propranolol, a β-blocker with

anxiolytic properties, reversed the tumor-promoting effects.

Similar results were observed in mice exposed to psychosocial

stress through crowded or isolated housing conditions where

stress-enhanced melanoma and fibrosarcoma growth was

decreased by the oral administration of propranolol.

In a social

defeat model in mice; we observed stress-elevated plasma corti-

costerone levels and an increase in the expression of glucocorti-

coid-inducible factor Tsc22d3 that blocked type I Interferon (IFN)

responses in dendritic cells (DC) and T cells, thus dampening

therapeutic responses against carcinogen-induced and transplan-

table tumors. In this setting, the administration of a glucocorticoid

receptor antagonist reversed the negative impact of psychosocial

stress on therapeutic outcomes.

Taken together, these findings

suggest that effectively preventing or managing psychological

stress by pharmacological strategies could significantly improve

oncological prognosis. However, putative effects of psychological

and medical stress on cancer induction and progression are cur-

rently discussed, and additional clinical data are expected to sup-

port this evidence and to further substantiate cause–effect

relationships

14,33,34

Preclinical investigations

β-ARs can be found on the cell surface of different types of

primary and metastatic tumor cells directly linking persistent

stress with oncogenesis and disease progression.

17,35–40

Thus,

epinephrine, norepinephrine, and other AR agonists can directly

act on malignant cells, leading to various pro-tumorigenic effects

including enhanced proliferation and increased migratory

potential.

18,35,37,39,41–43

These stress mediators also cause intra-

cellular hypermetabolism, as evidenced by the accumulation of

lipid droplets in MCF-7 breast cancer cells treated with AR

agonists in vitro.

44,45

Several downstream molecular mediators

have been identified as responsible for pro-tumorigenic β-AR

signaling, including the intracellular second messengers cAMP

and PKA, which transactivates epidermal growth factor receptor

(EGFR)

and triggers the initiation of the mitogen-activated

protein kinase 1 (MAP2K1 better known as MEK1)/mitogen-

activated protein kinase 1(MAPK1) and MAPK3 (better known

as ERK1/2) cascade

thus stimulating cyclin D1, cyclin E2, and

cyclin-dependent kinases CDK 4/6 to promote proliferation.

Moreover, β-AR signaling leads to the activation of cytosolic

phospholipase-A2, the release of arachidonic acid (AA), as well

as to an increased expression of the AA-metabolizing and

tumor-growth-promoting enzymes cyclooxygenase-2 (COX-2)

and 5-lipoxygenase in cancer cells.

48–50

PKA also upregulates

transcription factors including nuclear factor kappa B (NF-kB),

activator protein 1 (AP1), and cAMP response element-binding

protein (CREB) in the context of lung and pancreatic adenocar-

cinoma development.

Additionally, β-AR activation results in

enhanced retinoblastoma protein phosphorylation and sup-

presses Rap1B prenylation, leading to reduced cell–cell adhesion

and a migratory phenotype.

35,38,42,46,52

Interestingly, the auto-

crine secretion of epinephrine by certain cancer cells can stimu-

late β-AR, and this effect is further increased by oncogenic

factors such as nicotine.

53,54

Altogether these observations sup-

port the hypothesis that β-AR antagonists have clinical potential

by halting malignant disease and decreasing the incidence of

recurrences as suggested by the inverse correlation between the

incidence of prostate adenocarcinoma and the use of antihyper-

tensive drugs including β-blockers (n = 2442, HR = 0.7, 95%

[0.5–0.9]).

The exploration of different types of β-AR has been subject

to extensive research. However, among cardioselective β-

blockers, the nonselective propranolol appears to be particu-

larly effective.

Propranolol acts on both β1 and β2 receptors

and showed the capacity to effectively mitigate oxidative stress

as well as pro-tumorigenic inflammatory response such as IL-6

and TNF-α production.

57,58

Additionally, propranolol impairs

tumorigenesis in a time- and concentration-dependent manner

through various molecular and cellular processes.

42,59–61

Moreover, AR antagonists, including propranolol, have

shown potential to reverse stress-induced tumorigenesis and

disease progression.

19,35–39,41,52,62,63

Thus, by blocking β-adre-

nergic signaling and counteracting the metastatic potential of

epinephrine and norepinephrine, propranolol inhibits the

invasion of malignant cells and reduces their metastatic spread

to distant organs.

Propranolol can intercept voltage-gated

sodium channels expressed in malignant cells that are crucial

for cell mobility and additionally impair the enzymes MMP2

and MMP9, which dysregulate anti-tumor immunity and facil-

itate the migration of malignant cells through the extracellular

space.

65–67

Moreover, AR antagonists can halt cellular prolif-

eration through anti-mitotic effects paralyzing the cell cycle at

G0/G1/S phase or G2/M phase, strongly affecting DNA

synthesis.

68–76

AR antagonists also exhibit antiangiogenic

properties by decreasing the expression and activity of vascular

endothelial growth factor (VEGF) thus further impacting can-

cer progression.

66,77,78

Of note β-blockers can induce distinct types of cellular

stress including autophagy,

79,80

endoplasmic reticulum (ER)

stress and mitochondrial dysfunction resulting in the

4K. CARNET LE PROVOST ET AL.

production of reactive oxygen species (ROS) and affecting

glucose metabolism,

81,82

altogether triggering apoptotic or

necro(pto)tic cell death

83–90

of cancer cells. In addition,

these stresses deeply contribute to the anti-cancer

response,

especially by enhancing immune infiltration of

the tumor microenvironment.

92–94

AR antagonists also exert

trans-inhibitory effects on certain signaling pathways and

transcription factors involved in carcinogenesis. Epidermal

growth factor receptor (EGFR) is frequently overexpressed in

epithelial tumors, resulting in elevated levels of intracellular

cAMP and PKA, which promotes angiogenesis, invasiveness,

and renders cells resistant to apoptosis. Both propranolol and

atenolol can prevent the development and progression of

tumors by competitively decreasing intracellular cAMP and

PKA levels.

18,95

Moreover, propranolol can arrest the cell

cycle in various malignant cell types by downregulating

components of the pro-invasive signaling pathways ERK/

COX-2 or EGFR-Akt/ERK1–2, as well as by modifying the

phosphorylation level of survival (Akt, p53, GSK3β) and

mitogenic regulators (p44/42 MAPK, p38 MAPK, JNK,

CREB), ultimately leading to cancer cell

apoptosis.

35,47,59,68,69,96–99

Finally, β-AR antagonists have

been shown to reverse nicotine-induced mitogenic and pro-

tooncogenic factors such as COX-2, ERK1/2, PGE2, PKC,

and VEGF in colon, gastric, and lung cancer cells in

a dose-dependent manner.

54,100,101

Carvedilol, yet another β- and β-AR antagonist, exerts cyto-

toxic effects on many human hematopoietic and solid tumor

cell lines.

102

Compared with other adrenergic agents, carvedilol

exhibits a unique Ca

mobilization capacity by exerting con-

trol over extracellular Ca

influx and the release of Ca

from

ER stores. The carvedilol-orchestrated increases in cytosolic

movement triggers cytotoxicity and inhibits the migra-

tory capacity of human osteosarcoma, hepatoma and oral

cancer cells in a concentration-dependent manner.

85,87,103

Carvedilol inhibits signaling pathways promoting invasiveness,

including the cAMP, PKA/SCR, PKCs/Src pathways.

104

Moreover, carvedilol inhibits EGF-mediated malignant skin

transformation in a dose-dependent manner by impairing

AP-1 activation.

105

Conversely, atenolol, another β1-AR spe-

cific antagonist, failed to prevent neoplastic transformation

after application to mouse epidermal cells JB6 P.

+105

Until now β3-AR blockade was less investigated. However,

an increased expression of β3-AR was reported for neuroblas-

toma and melanoma.

Moreover, β3-ARs favor the recruit-

ment of tumor-associated pro-inflammatory and pro-tumor

effectors such as fibroblasts and M2 macrophages. The use of

β3-AR antagonists, such as SR59230A and L-748 337, report-

edly impacts tumor vasculature and reduces the growth of

melanoma.

86,106

SR59230A induces a significant reduction of

mitochondrial activity, halting ATP synthesis and triggering

the generation of reactive oxygen species, resulting in tumor

cell death.

107

Moreover, the inhibition of β3-AR reduces the

proliferation of neuroblastoma by dysregulation of bioactive

lipid sphingosine kinase 2/sphingosine 1-phosphate metabo-

lism, which is implicated in various cancers and anticancer

therapy resistance.

108

Furthermore, β3-AR antagonists were

shown to reduce the phosphorylation of the mTOR/p70S6K

pathway, thus reducing malignant growth.

109

β-AR antagonists have shown a significant potential in

mitigating the immunosuppressive effect of chronic stress,

thereby improving immunosurveillance. Thus, propranolol

was shown to suppress stress-induced lung metastases in

a preclinical model of murine breast cancer, while nadolol

decreased the incidence of metastases promoted by surgical

stress by 50%.

61,110,111

In various models of subcutaneous

cancers, propranolol prevented a stress-induced ileopathy

that led to immunosuppressive dysbiosis.

112

Propranolol

also suppresses the progression of hematopoietic cancers

such as acute lymphoblastic leukemia by impairing α-adre-

nergic signaling activated during psychological stress.

113

Furthermore, α-blockers decrease the number of myeloid-

derived suppressor cells (MDSCs). Conversely, MDSCs are

induced by α2 adrenergic signaling in response to chronic

stress.

114–118

β-adrenergic receptors play an important role in shaping the

immune orientation of the tumor microenvironment.

119,120

Thus, decreasing adrenergic stress by different approaches

including physiological manipulation such as placement of

mice in a thermoneutral environment, genetic interventions

such as the knockout of β-AR or pharmacological β-blockade,

increases glycolysis and oxidative phosphorylation in tumor-

infiltrating lymphocytes. Reduction of adrenergic stress upre-

gulates the expression of the costimulatory molecule CD28,

stimulates cytokine release

121

and enhances the ration of cyto-

toxic over regulatory T cells. It also increases the secretion of

granzyme B and IFN-γ contributing to immune-mediated anti-

cancer responses in mice.

96,99,122

Additionally, SR59230A pro-

motes the differentiation of stromal cells and increases the

abundance of lymphoid, myeloid, and NK progenitor cells in

the tumor microenvironment. Altogether, these effects may

inhibit tumor progression, inflammation and angiogenesis.

123

Propranolol has demonstrated a remarkable synergism with

current antineoplastic therapies. Specifically, it enhances radio-

sensitivity, thereby increasing radiotherapy-induced abscopal

antitumor effect and exerts T cell-dependent immune response

that effectively slows tumor growth. Moreover, propranolol

decreases the expression of prometastatic, proinflammatory

and proangiogenic genes such as EGFR, COX-2 and VEGF,

respectively, thus impairing cell viability and inducing

apoptosis.

60,124–127

The cytotoxic effects of conventional chemotherapeutic

agents such as platinum salts, anthracyclines (such as doxor-

ubicin), 5-fluorouracil, mitotic spindle poisons (such as tax-

anes or vincristine), topoisomerase inhibitors and gemcitabine

were increased in the presence of β-blocking agents including

propranolol.

128–134

β-blocking agents also boosted the antic-

ancer effect in combination with targeted therapies such as

U0126 (a MAPK inhibitor),

sorafenib (a multikinase

inhibitor),

vemurafenib (a B-Raf gene inhibitor),

135

and suni-

tinib (an inhibitor of tyrosine kinase).

136

Importantly, propra-

nolol was found to decrease the expression of programmed

death receptor-1 (PD-1) in tumors and to increase CD8

T cell

infiltration within the tumor microenvironment, thus enhan-

cing the efficacy of immune checkpoint blockade.

93,122,137–142

If combined with the antitumor vaccine STxBE7, propranolol

strongly enhanced the amount of tumor infiltrating CD8

T cells, although without improving their activity.

143

ONCOIMMUNOLOGY 5

Even agents without any direct antitumor activity have been

found to potentiate the cytotoxic effects of β-blockers. Thus,

the combination of propranolol with metformin, an oral anti-

diabetic agent, revealed an unexpected synergistic inhibitory

effect on proliferation, invasion, and migration in vitro and

reduced tumor growth and metastasis in vivo.

144,145

Similarly,

when combined with the COX-2 inhibitor etodolac, proprano-

lol increased the cytotoxicity of NK cells, reduced postsurgical

local relapse and metastasis and improved overall free-

survival.

146–148

In conjunction with 2-deoxy-D-glucose

(2DG), propranolol significantly reduced glucose metabolism

associated with alterations in mitochondrial morphology and

the subsequent activation of endoplasmic reticulum stress,

autophagy, proliferative arrest ultimately resulting in

apoptosis.

149

Altogether, this underscores the potential of AR

blocking agents alone or in combination with additional med-

ication as novel anticancer (immuno)therapies. Table 2,

Figure 2.

Published clinical trials

The aforementioned preclinical findings spurred the initiation

of numerous clinical trials most of which are observational (12

retrospective trials, 1 prospective trial and 6 meta-analyses).

Retrospective studies come from cohorts of oncological patients

treated with β-blockers for a history of cardiovascular disease or

arterial hypertension or from data extracted of prospective trials

with incidental use of β-blockers. Most of the results concluded

to a positive impact of β-blockers on oncological outcomes. β-

blockers significantly decreased tumor growth and the risk of

metastasis into distant organs. As a result, most analyses

reported a strong positive correlation between the use of β-

blockers and overall and progression free-survival in various

treated solid tumors.

150–161

These positive and encouraging

results need to be confirmed in prospective randomized con-

trolled trials. Indeed, these studies involved many sources of bias

such as combination of antihypertensive drugs (β-blockers plus

angiotensin-II-receptor inhibitor or angiotensin-converting

enzyme inhibitors) and positive effects of β-blockers on cardio-

vascular mortality. Only three trials failed to report prognostic

effects of β-blockers

162–164

except a better response to pembro-

lizumab in the treatment of stage III melanoma.

162

Only one

study reported negative effects of β-blockers in a cohort of HER2

+ breast cancer patients treated with trastuzumab, where

β-blocker appeared to decrease survival (PFS adjusted HR =

2.21, 95%[1.56–3.12]; p < 0.001 and OS adjusted HR = 2.46,

95%[1.69–3.57]; p < 0.001)

165

. However, the higher rate of mor-

tality observed in this trial might involve cardiovascular mortal-

ity or immune toxicity. Table 3

Nine prospective interventional or randomized controlled

trials have been published. One study enrolled 25 participants

with multiple myeloma to receive either propranolol in titrated

doses or placebo for 5 weeks. This trial concluded on the

tolerability and the efficacy of propranolol to minimize β-

adrenergic stress during hematopoietic cell transplantation. It

also showed successful engraftment and effective response

against myeloma when propranolol was administered.

166

Safety and efficacy of β-blockers on adrenergic stress during

the treatment of 26 ovary cancers were also confirmed.

167

Used

as a standalone agent during breast cancer and melanoma care,

propranolol increases immune cell infiltration into the tumor

bed and significantly reduces the risk of recurrence.

168,169

When associated with conventional antineoplastic treatments

such as taxanes or anthracyclines, β-blockers are also perfectly

tolerable and safe.

170

Moreover, propranolol potentiates the

immune effects of pembrolizumab against melanoma.

171

Combined with anti-COX-2 during the peri-operative period

of breast and colorectal cancer surgery in three randomized

controlled trials, propranolol minimizes surgical stress,

improves tumor molecular markers, reinforces the anti-

tumor immune response, impairs pro-inflammatory and meta-

static transcription factors and finally decreases the risk of

relapse.

172–175

Finally, a few prospective studies all reported promising

oncological outcomes. Thus, the study of Ramondetta et al.

showed that patients with ovary cancer treated with proprano-

lol had 55.5% complete response, 33.3% partial response, 5.6%

stable response, and only 5.6% progressive disease

165

. In the

randomized controlled trial by De Giorgi et al. the administra-

tion of β-blocker to patients with melanoma decreased the risk

of recurrence (80%, HR = 0.18, 95% CI [0.04–0.89], p = 0.03)

with a DFS 89% vs 64% (p = 0.04). Treatment with β-blocker

also decreased the rate of progressive disease (15.8% vs 41.2%)

and death (10.5% vs 17.7%).

167

Associated with pembrolizu-

mab, β-blockers allowed to achieve 7 partial responses and 1

stable disease in a cohort of 9 metastatic melanoma patients.

169

Of note, four studies notified cardiovascular events such as

hypotension and bradycardia due to the consumption of

β-blockers without major consequences.

164,166,168,169

Table 4

Completed clinical trials

The primary focus of these trials was to study the effect of β-

blockers as standalone agents. Among these trials,

NCT01544959 evaluated the possibility of substituting fentanyl

with esmolol for anesthesia induction, followed by metoprolol

during mastectomy, with the aim to manage hemodynamic,

perioperative pain and postoperative nausea and vomiting.

NCT02596867, a non-randomized phase II trial, studied the

effect of β-adrenergic blockade with 0.75 mg/kg propranolol,

administered twice daily for 3 weeks, prior to surgical resection

of breast cancer. The trial assessed the tumor proliferative

index using Ki-67 before and 3 weeks after propranolol admin-

istration and assessed the capacity of propranolol to decrease

tumor proliferation in breast cancer. Similarly, the early phase

I study NCT02013492 evaluated the potential of propranolol

administered for 4 weeks in patients with locally-recurrent or

metastatic solid tumors to decrease tumor growth by inhibiting

the effects of adrenergic hormones on the tumor cells.

Furthermore, the study NCT03861598 aimed at establishing

a correlation between circulating tumor cells and favorable

magnetic resonance imaging (MRI) results in patients with

grade IV glioblastoma receiving chemotherapy with

a combination of escalated doses of carvedilol. Further trials

investigated whether the synergistic effects observed between

β-blockers and conventional chemotherapies observed in pre-

clinical studies were assessable in clinical practice. Both

NCT01308944 and NCT01504126 aimed at confirming

6K. CARNET LE PROVOST ET AL.

Table 2. Antitumor eﬀects of β-blockers.

Cancer type β-blocker Cell lines; animal model; patient sample Mode of action Ref.

Angiosarcoma,

hemangio-

endothelioma

Propranolol Murine angiosarcoma SVR and

hemangioendothelioma EOMA cells; canine

angiosarcoma Emma, Frog and SB cells

Concentration-dependent inhibition of proliferation,

migration and tumor growth; apoptosis induction

Bone sarcoma Propranolol, carvedilol Canine osteosarcoma OSCA 32, OSCA 40 cells;

human osteosarcoma HOS cells and Ewing

sarcoma A673 cells

Concentration-dependent inhibition of viability;

enhanced radiosensitivity

Breast cancer Atenolol,

L-748,337

(β3 antagonist)

Human breast cancer MCF-7 cells Reduced adrenaline and isoprenaline induced lipid

droplets cAMP, PKA, EPAC-dependent way

Breast cancer Propranolol Murine breast tumor 4T1 cells Reduction of inducible MDSC in vitro; inhibition of IL-

6 expression

116

Breast cancer, colon

cancer,

melanoma

Propranolol Murine CT26.CL25, B16-F10, 4T1 cells, C57BL/6 and

BALB/c mice

Potentiation of abscopal antitumor eﬀects and T cell

immune responses to radiotherapy; reduction of

metastasis

124

Breast cancer Propranolol Murine breast cancer 4T1 and AT-3 cell, C57BL/6 and

BALB/c mice

Reduction of MDSCs and impairment of

immunosuppressive function

114

Breast cancer Propranolol Human breast cancer MDA-MB-231 cells Inhibition of voltage-gated sodium channels,

inhibition of lateral motility and invasion

Breast cancer Propranolol, ICI 118,551

(selective β2 blocker)

Human breast cancer MDA-MB-231 cells Inhibition of viability by downregulation of ERK, COX-

2 pathways; cell cycle arrest; apoptosis

Breast cancer Propranolol Murine breast cancer 4T1 cells, BALB/c, NSG and

C57BL/6 mice

Suppression of stress-induced lung metastasis

110

Breast cancer Propranolol Murine breast cancer 4T1 cells, BALB/c and C57BL/6

mice

Increased CTL/Treg ratio and decrease PD-1

expression in the TME; potentiation of anti-PD-1

checkpoint blockade

122

Breast cancer Propranolol Human breast cancer MDA-MB-231, IBH-6 cells Inhibition of migration

Breast cancer Propranolol Human breast SK-BR-3 cells Anti-proliferation; decreased p44/42 MAPK, p38

MAPK, JNK, and CREB signaling, increased

phosphorylation of survival/apoptosis regulators

AKT, p53, and GSK3β).

Breast cancer Propranolol Human breast M-406, MCF7, MDA-MB-231 cells;

murine breast cancer M-234p, 4T1 cells; BALB/c

and CBi mice

Synergistic eﬀects with metformin, inhibition of

viability, migration, invasion, mitochondrial

function, tumor growth and metastasis

144

Breast cancer Propranolol; CGP-20712A

(β1 antagonist);

ICI-118,551; L-748,337

Human breast cancer MDA-MB-231 cells; BALB/c

nude mice

Inhibition of invadopodia formation (role in invasion

via Src pathway)

186

Breast cancer Propranolol Human breast cancer MDA-MB-231 cells Inhibition of migration

Breast cancer Carvedilol Human breast cancer MDA-MB-231 and MCF-7 cells Inhibition of migration and invasion via inhibition of

Src pathway

104

Breast cancer Propranolol Murine breast cancer 4T1 cells, human breast cancer

MDA-MB-231 and MCF-7 cells

Decreased HK-2 expression; inhibition of glucose

metabolism

187

Breast cancer Propranolol Human breast cancer MDA-MB-231, MDA-MB-468,

MDA-MB-435S cells

Reversed norepinephrine-mediated adhesion

promoted by the release of GROα and β1 integrin

Breast cancer Propranolol Human breast cancer MCF-7, MDA-MB-231 and

SKBR3 cells, glioblastoma U87 cells, lung

carcinoma A549 cells, neuroblastoma SK-N-SH

cells; NMRI nude mice

Anti-proliferation (dose-dependent); anti-

angiogenesis; synergistic eﬀect in vitro and in vivo

with 5-ﬂuorouracil and paclitaxel in cell type and

dose dependent manner

128

Breast cancer Propranolol Human estrogen responsive breast cancer MCF-7,

ZR-75, MDA-MB-361; estrogen non-responsive

breast cancer MDA-453, MDA-435, MDA-468 cells

Short exposure of MDA-453 to propranolol increases

GIRK1 mRNA (potassium channel) and decrease

B2-adrenergic mRNA levels

188

Breast cancer Atenolol, propranolol, ICI

118,551

Human estrogen responsive breast cancer MCF-7,

ZR-75, MDA-MB-361; estrogen non-responsive

breast cancer MDA-453, MDA-435, MDA-468 cells

Inhibition of DNA synthesis

Cervical cancer Propranolol Human cervical carcinoma Siha, HeLa cells Anti-proliferation by suppressing cGMP/PKG

pathway; inhibition of clone formation; apoptosis

induction

Colorectal cancer Propranolol Human colorectal cancer HCT116, HT29, RKO cells Apoptosis induction; decreased mitochondria and

proteins involved in oxidative phosphorylation;

reduced metastatic potential, viability and

proliferation

Colorectal cancer Propranolol Murine colorectal cancer CT26 cells; BALB/c mice Decreased tumor growth by activating CD8

T cells

and by inhibiting AKT/MAPK pathway

Colorectal cancer Atenolol, carvedilol,

propranolol, ICI 118,551

Human colorectal cancer HT-29 cells Reversion of AR agonists-induced proliferation

Colorectal cancer Propranolol Murine colorectal cancer CT26 cells; BALB/c mice Improved resistance to metastasis in combination

with etodolac

146

Colorectal cancer Atenolol, propranolol, ICI

118,551

Human colorectal cancer SW1116, SW480, SW620,

DLD1, HCT116, Colo205, HT29 cells, BALB/c mice

Inhibition of viability and tumor growth (G1-phase

cell cycle arrest and inhibition of EGFR-Akt/ERK1/2

pathway), apoptosis induction

Colorectal cancer Atenolol, ICI 118,551 Human colorectal cancer HT-29 cells Dose-dependent inhibition of nicotine-induced

tumor growth, microvessel densities; expression of

COX2, PGE2, VEGF

100

Colorectal cancer Atenolol, propranolol Human colorectal cancer SW 480 cells Inhibition of norepinephrine-promoted migration

(Continued)

ONCOIMMUNOLOGY 7

Table 2. (Continued).

Cancer type β-blocker Cell lines; animal model; patient sample Mode of action Ref.

Cutaneous

squamous-cell

carcinoma

Butoxamine (β2

antagonist), ICI 118,551

Human skin epidermoid carcinoma A-431 cells Inhibition of VEGF-A-induced angiogenesis;

decreased tumor development

Gastric cancer Propranolol Human gastric cancer MKN45, NUGC3 cells Inhibition of tumor growth, viability (G1 cycle arrest),

and migration; apoptosis induction; decreased

expression of P-CREB-ATF and MEK-ERK pathways;

suppression of MMP2, MMP9 and VEGF expression

Gastric cancer Propranolol

ICI 118,551

Human gastric cancer HGC27, MKN45, MGC803,

BGC823, SGC7901, AGS cells

G1/S phase cell cycle arrest; apoptosis; inhibition of

tumor growth, proliferation, invasion, and

metastasis by inhibiting ERK1/2-JNK-MAPK

pathway and transcription factors (NFkB, CREB,

STAT3)

Gastric cancer Propranolol Human gastric cancer SGC7901l cells; nude mice Potentiation of radiotherapy eﬀects, decreased

tumor growth, decreased expression of NFkB and

then COX-2, EGFR, VEGF expression)

125

Gastric cancer ICI 118,551 Human gastric cancer NCI-N87, MGC803, HGC27,

BCG823 cells

Decreased catecholamine-stimulated MUC4

expression involved in the resistance of

trastuzumab in HER2

gastric cancer

189

Gastric cancer Propranolol Human gastric cancer SGC7901, BCG823 cells Inhibition of proliferation (G0/G1 arrest and G2/M

arrest) in a concentration-dependent manner;

apoptosis; decreased expression of NFkB, VEGF,

COX-2, MMP2, MMP9

Gastric cancer Propranolol Human gastric cancer SGC7901, BCG823 cells Potentiation of radiation eﬀects, decreased viability

and clonogenic potential, apoptosis through the

inhibition of NFkB/VEGF/EGFR/COX-2 pathways

126

Gastric cancer Atenolol,

ICI 118,551

Human gastric cancer AGS cells Reversion of nicotine-induced expression of PKC,

ERK1/2 phosphorylation, and COX-2 with cell

proliferation

100

Glioma Propranolol C6 rat glioma Inhibition of TNFα-induced proliferation

190

Kidney cancer Propranolol, ICI 118,551 Patient derived ccRCC cells; human renal cell

carcinoma 786-O cells

Decreased viability; decreased oxidative stress and

mRNA expression of proinﬂammatory cytokines

Kidney cancer Propranolol, ICI 118,551 Human renal cell carcinoma 786-O cells; NSG mice Apoptosis induction; inhibited expression of HIF2α,

CAIX, VEGF; impaired nuclear internalization of

HIF2α and NFkB/p65, reduced tumor growth

Leukemia Propranolol Human leukemia Molt-4, Jurkat, U937 cells Decreased VEGF and MMP2 activity

Leukemia SR59230A

(β3 antagonist)

Human myeloid leukemia K562, KCL22, HEL, HL60

cells

Apoptosis induction, doxorubicin-resistance

reversion

123

Leukemia Propranolol Human pre-B acute lymphoblastic leukemia Nalm-6

cells; NCID mice

Reversed stress eﬀect of by decreasing tumor burden

and dissemination

113

Liver cancer Propranolol Murine hepatocellular carcinoma H22 cells; BALB/c

mice

Inhibition of tumor growth induced by chronic stress

and inactivation of CXCL5-CXCR2-ERK pathway

191

Liver cancer Propranolol Murine hepatocellular carcinoma H22 cells Inhibition of tumor growth; prevention of the

redistribution of splenic myeloid cells

Liver cancer Propranolol Human liver cancer HepG2, HepG2.2.15, HL-7702

cells

Anti-proliferation; apoptosis induction; S-phase cycle

arrest

Liver cancer Carvedilol Wistar rats with hepatic cirrhosis Decreased hepatocarcinogenesis by suppression of

circulating IL-6, ALT, AST, ALP, Bilm, and hepatic IL-

6, STAT-3, MDA levels and hydroxyproline content

192

Liver cancer Carvedilol Human hepatoma HA59T cells Increased intracellular calcium; apoptosis

Liver cancer ICI 118,551 HCC cell lines, C57BL/6 mice Autophagy; HIF1α destabilization; tumor growth

suppression; improved anti-tumor activity of

sorafenib

Lung cancer Atenolol, betaxolol,

esmolol, metoprolol,

pindolol, propranolol,

timolol

Human lung carcinoma A549, H1299 cells Apoptosis, necrosis induction; inhibition of lung

cancer cell colony formation

Lung cancer ICI 118,551 Human NSCC lung cancer UMSCC103, Cal33 cells Inhibition of p38 and NFkB oncogenic pathways;

aﬀect ERK and PI3K pathways, Nrf2-Keap1 stability

and its nuclear translocation; induction of ROS and

oxidative stress; synergistic eﬀect with U0126

(MAPK inhibitor) on viability and induction of

autophagy

Lung cancer Propranolol Patient-derived head and neck cancer cells Inhibition of proliferation and viability

Lung cancer Esmolol,

ICI 118,511, nadolol

Human lung cancer A549, MRC-5 cells Apoptosis

ROS induction

Lung cancer Propranolol Rat breast cancer MADB106 cells; F344 rats Combined with etodolac (COX-2 inhibitor): reduction

of tumor retention induced by surgery, increase

NK cytotoxicity

147

Lung cancer Nadolol Rat breast cancer MADB106 cells; F344 rats Decrease surgery-induced metastasis

111

Melanoma Propranolol, ICI 118,551 Murine melanoma B16F10 cells Inhibition of AR agonist induced proliferation

176

(Continued)

8K. CARNET LE PROVOST ET AL.

Table 2. (Continued).

Cancer type β-blocker Cell lines; animal model; patient sample Mode of action Ref.

Melanoma SR59230A Murine melanoma B16F10 cells Decreased tumor growth, proliferation and viability;

induced diﬀerentiation of stromal cells in the TME,

promote hematopoietic diﬀerentiation; increased

number of NK cells

129

Melanoma Propranolol Human melanoma MEL270, OMM2.5, MP41, MP46,

WM115, WM266.4 cells

Anti-proliferation; anti-migration; VEGF reduction;

cell cycle arrest; apoptosis

Melanoma SR59230A Human melanoma A375 cells Reversion of reduction of mitochondrial activity

mediated by β3-AR/UCP2 axis

107

Melanoma Propranolol Human melanoma A375 cells; patient derived-

melanoma cells; NOD/SCID mice

Synergistic eﬀect with sunitinib (anti-proliferation,

cell cycle arrest through suppressing ERK/Cyclin

D1/Rb/Cyclin E, decrease tumor growth)

136

Melanoma Propranolol MT/ret mice Decreased angiogenesis, proliferation and survival;

decreased inﬁltration of immunosuppressive

myeloid cells in TME

115

Melanoma Propranolol Human melanoma A375 cells, patient derived

melanoma cells; BALB/c mice

Cell cycle arrest; apoptosis via AKT/MAPK pathway

Melanoma L 748,337 Murine melanoma B16F10 cells Decreased tumor growth, neoangiogenesis and

proliferation; increased tumor cell death

106

Melanoma Propranolol Patient derived melanoma cells Anti-proliferation; anti-angiogenesis; apoptosis;

decreased tumor growth

Melanoma SR59230A

L 748,337

Murine melanoma B16F10 cells Anti-proliferation; apoptosis; decreased tumor

growth

Melanoma Propranolol Human melanoma A375, Hs29-4T cells Decrease mobility and released IL6/VEGF induced by

catecholamines

Melanoma Metoprolol,

Propranolol,

ICI 118 551

Murine melanoma B16F10 cells Potentiation of anti-PD-1 checkpoint blockade

137

Multiple myeloma Bisoprolol,

Propranolol

ICI 118 551

Human multiple myeloma LP-1, OPM-2, RPMI-8226,

ANBL-6, XG-2 cells

Apoptosis; autophagy; mitochondrial respiratory

chain alteration; decreased glycolysis; increased

chemosensitivity to melphalan and bortezomib

193

Neuroblastoma Propranolol Human neuroblastoma KELLY, CHLA-20, LAN-5, IMR-

32, SK-N-BE1, SK-N-BE

, SK-N-BE

c, SK-N-SH, SK-

N-AS, LAN-6, SH-EP, CHLA-15, CHLA-90, SK-N-FI

cells

Inhibition of growth and proliferation; apoptosis via

activation of p53 and p73; synergistic eﬀect with

SN-38 (topoisomerase I inhibitor)

130

Neuroblastoma Atenolol, butoxamine,

carvedilol, labetalol,

metoprolol nebivolol,

propranolol

Human neuroblastoma BE

-C, SHEP, SK-N-SH cells Synergistic eﬀect with vincristine (anti-angiogenic,

anti-mitochondrial, anti-mitotic, pro-apoptotic

eﬀects, decrease tumor growth)

131

Neuroblastoma SR59230A Human neuroblastoma SK-N-BE

and BE

C cells;

murine neuroblastoma Neuro-2A cells; NCI A/JCr

mice

Decreased proliferation; inhibition of tumor growth

and progression through blockade of SK2/S1P

signaling

108

Neuroblastoma SR59230A Neuroblastoma cell lines from patients Anti-proliferation; Inhibition of tumor growth and

colony formation through the inactivation of the

mTOR/p70S6K pathway

109

Osteosarcoma Carvedilol Human osteosarcoma MG63 cells Anti-proliferation

Increase in intracellular calcium level, which may lead

to cytotoxicity

103

Osteosarcoma Propranolol Human osteosarcoma MG63, U2OS cells Decreased tumor growth; anti-mitotic; G0/G1 cycle

arrest; impaired colony formation, 3D spheroid

growth, cell chemotaxis and capillary-like tube

formation; alteration of cytoskeleton

OSCC Propranolol Human tongue cancer SCC-9, SCC-25, Cal27 cells Dose- and time-dependent decrease in viability;

downregulated p-P65 NFkB and VEGF expression;

inhibited cell migration; synergism with CDDP and

5-FU

132

OSCC Propranolol OSCC cells; BALB/c mice Reversed anti-migratory eﬀect induced by AR agonist

OSCC Propranolol 4NQO induced oral carcinogenesis in Wistar rats Decreased occurrence of tumors; decreased thickness

of OSCC; reduced pro-inﬂammatory cytokines IL-6

and TNF-alpha

OSCC Propranolol Human tongue cancer SCC-9, SCC-25 cells Reversion of migratory eﬀect of norepinephrine

OSCC Carvedilol Human oral cancer OC2 cells Apoptosis

OSCC Propranolol Human tongue cancer TCa8113 cells; human salivary

adenoid cystic carcinoma ACC cells

Reversed migratory and mitogenic eﬀect of

norepinephrine

Esophagus cancer Atenolol,

ICI 118,551

Human esophageal squamous cell carcinoma

HKESC-1 cells

Reversion of proliferative eﬀect of epinephrine

Esophagus cancer Atenolol,

ICI 118,551

Human esophageal squamous cell carcinoma

HKESC-1 cells

Inhibition of proliferative eﬀects mediated by

epidermal growth factor

Ovary cancer Propranolol Murine ovarian cancer HeyA8, SKOV3ip1, A2780,

RMG-II, MB-231 cells

Reversion of AR agonist and daily stress-induced

tumor growth and angiogenesis.

Pancreas cancer ICI 118,551, metoprolol Human pancreatic adenocarcinoma MIA PaCa-2,

BxPC-3 cells

G1/S phase cell cycle arrest; apoptosis; anti-

proliferative, anti-invasive eﬀect

(Continued)

ONCOIMMUNOLOGY 9

feasibility of administering β-blockers before, during and after

surgical ovarian cancer debulking until completion of che-

motherapy to mitigate depression and anxiety and to evaluate

an impact on immune response and survival. The randomized

multicenter phase 2 study NCT01857817 was designed to eval-

uate clinical benefits and changes in circulating prostate-

Table 2. (Continued).

Cancer type β-blocker Cell lines; animal model; patient sample Mode of action Ref.

Pancreas cancer Atenolol, propranolol, ICI

118,551

Pancreatic ductal adenocarcinoma patient cohort Synergistic eﬀects with gemcitabine on survival

133

Pancreas cancer Propranolol Human pancreatic carcinoma Panc-1 cells Reversion of pro-tumor eﬀects of norepinephrine

Pancreas cancer Propranolol Human pancreatic cancer Colo-357, BxPC-3, MIA

PaCa-2, Panc-1, PaTus cells; murine pancreatic

cancer 6606PDA, TD1, TD2, Panc02 cells; C57BL/6

mice

Reversion of catecholamine-induced proliferation

and migration

Pancreas cancer ICI 118,551 Human pancreatic cancer BxPC-3, MIA PaCa-2 cells Synergistic eﬀect with gemcitabine (anti-proliferative

and pro-apoptotic eﬀects); inhibition of NFkB

134

Pancreas cancer Metoprolol, propranolol,

ICI 118,551

Human pancreatic cancer BxPC-3, MIA PaCa-2 cells Anti-proliferative and anti-invasive eﬀect by

inhibition of cAMP/PKA and Ras, NFkB, AP-1, CREB,

VEGF, MMP2, MMP9, COX-2

Pancreas cancer Propranolol Human pancreatic cancer BxPC-3, MIA PaCa-2 cells Reversion of the invasive eﬀect of norepinephrine

(concentration-dependent)

Pancreas cancer Propranolol Nitrosamine-induced pancreas cancer in Syrian

golden hamsters

Anti-tumor eﬀect by blocking cAMP-dependent

intracellular signaling, cAMP-dependent release of

EGF and PKA-dependent release of VEGF

Pancreas cancer Butoxamine, metoprolol,

propranolol

Human pancreatic adenocarcinoma PC-2 cells Apoptosis

Pancreas cancer Propranolol Human pancreatic adenocarcinoma Panc-1 cells Reversion of the pro-tumor eﬀect (tumor growth) of

AR agonist

Pancreas cancer Propranolol Human pancreatic adenocarcinoma Panc-1, HPAF-II,

Capan-1 cells; BALB/c-Foxn1nu mice

Reversion of proliferative and invasive eﬀects

induced by the activation of AR by chronic stress

Prostate cancer Propranolol Human pancreatic adenocarcinoma PC-3 cells Propranolol + 2DG (glycolysis inhibitor) induced

autophagy, anti-proliferative eﬀects, apoptosis,

mitochondrial morphology alteration,

endoplasmic reticulum stress, and suppression of

tumor growth

149

Prostate cancer Propranolol Human pancreatic adenocarcinoma PC-3 cells; BALB/

c mice

Reversion of norepinephrine-induced lumbar lymph

metastasis

Prostate cancer ICI 118,551 Human prostate cancer C42 cells Prevention of stress-induced eﬀects

194

Bladder cancer,

prostate cancer

Propranolol Human prostate cancer C4, human prostate cancer,

human urinary bladder carcinoma T24 cells

Apoptosis; inhibition of MAPK pathway

Thyroid cancer Propranolol Human thyroid cancer K1, BCPAP, ATC, BHP27 cells Inhibition of tumor growth; apoptosis; cell cycle

arrest; decreased expression HK2 and GLUT1;

Synergism with vemurafenib

135

Uveal melanoma Carvedilol Human uveal melanoma Mel270, 92–1, UPMD2,

UPMM3 cells

Inhibition of tumor growth; prevention of long-term

survival; additive cytotoxic eﬀect with radiation

127

Colorectal cancer,

melanoma

Propranolol Murine melanoma B16-OVA cells, colorectal cancer

CT26.CL25 cells; C57BL/6NCr and BALB/c mice

Decreased tumor growth in stressed mice; reduced

checkpoint receptors; increased glycolysis/

mitochondrial dysfunction, oxidative

phosphorylation and CD28 expression in TILs;

increased expression of anti-tumor cytokines

121

Lung cancer, skin

cancer

Carvedilol Murine epidermal cancer JB6 P

cells; human lung

cancer A549 cells

Inhibition of EGF-induced malignant transformation;

inhibition of EGF-mediated activator protein-1

(AP-1) activation

105

Breast cancer,

Colorectal cancer,

liver cancer

Atenolol, propranolol, ICI

118,551

Human breast cancer MCF7, colorectal cancer HT29,

liver cancer HepG2 cells

Anti-proliferative, anti-migratory and anti-invasive

eﬀect

Lung cancer,

melanoma

Propranolol Murine melanoma B16F10.9,

Lewis lung carcinoma 3LL cells; C57BL/6J mice

Combined with COX-2 inhibitor etodolac: improved

overall survival and recurrence free-survival;

reversed surgical glucocorticoid stress: increase NK

cytotoxicity and expression of Fas ligand and

CD11a; decreased corticosterone level

148

Breast cancer, cervix

adenocarcinoma,

melanoma,

leukemia

Carvedilol Human breast cancer MDA-MB-231; melanoma Fem-

x; cervix adenocarcinoma HeLa, leukemia K562

cells

Anti-proliferative eﬀect

102

Fibrosarcoma,

melanoma

Propranolol Murine melanoma B16, ﬁbrosarcoma Meth A cells;

C57BL/6 and BALB/c mice

Inhibit psychological stress-enhanced tumor growth

/ Atenolol, propranolol, ICI

118,551

Preclinical in vivo model (xenografts) Inhibition of cell viability and xenograft growth;

decreased phosphorylation of AKT/MEK/ERK;

activation of CD8

T cells in TME

/ Propranolol Mouse model of vaccine-based immunotherapy

(C57BL/6J and OT-IxSJL) + TC1 expressing HPV16-

E6/E7

Improved eﬃcacy of antitumor STxBE7 vaccine by

enhanced the CD8

T cell inﬁltration

143

10 K. CARNET LE PROVOST ET AL.

specific antigen (PSA) of the VT-122 protocol consisting of

a co-administration of 22 mg propranolol plus etodolac 340 mg

in clinically progressive prostate cancer. Table 5

Ongoing clinical trials

Most registered currently ongoing studies aim at evaluating the

clinical impact, in particular overall survival and disease-free

survival, after administration of β-blockers during the manage-

ment of various solid tumors and hematological malignancies.

Some of these trials also investigate potential advantages aris-

ing from the combination of β-blockers with additional antic-

ancer or non-anticancer agents.

β-blockers as single agents

The randomized placebo-controlled clinical trial

MELABLOCK (NCT02962947) is designed to evaluate the

efficacy and safety of a daily dose of 80 mg propranolol in

patients with stage II/IIIA melanoma. NCT04518124 consists

of a single arm propranolol administered in a dose of 40–80 mg

2–3 times per day immediately after diagnosis of cutaneous

angiosarcoma extending over a period of 3–6 weeks. Clinical

and histological responses defined as a decrease in Ki-67 index

will be measured until study completion. The early phase

I interventional trial NCT03245554 intends to enroll in total

80 patients with gastric adenocarcinoma or non-metastasized

colon cancer without any prior treatment. Propranolol will be

administered for 1 week as a neoadjuvant treatment during the

preoperative period and CT-scan and Ki-67 index will be used

to evaluate tumor growth. NCT02944201 aims to investigate

whether β-blockers administered to prostate cancer patients

from the point of diagnosis until prostatectomy can decrease

tumor growth measured by Ki-67 index and TUNEL assay

performed on prostatectomy tissues. Notably, the phase II

study NCT05679193 presents as a large randomized controlled

trial that aims to assess the potential of a 3 weeks propranolol

regimen in reducing recurrences after robot-assisted laparo-

scopic prostatectomy, a surgical procedure significantly less

inflammatory and stressful as compared to conventional lapar-

otomy. The study will assess changes in catecholamines and

PSA levels during the perioperative period, the bioavailability

of propranolol as well as the impact on anesthesiological and

surgical strategies including the use of vasopressors, and the

occurrence of complications. Finally, NCT05312255 focuses

on the evaluation of immune effects, stress reduction and

quality of life in non-chemotherapeutic interventions such

as physical activity, specific nutritional regimen and propra-

nolol treatment in patients with multiple myeloma.

β-blockers combined with conventional anticancer

therapies

Four interventional clinical trials are planned to examine safety

and efficacy of propranolol administered in combination with

conventional chemotherapy to potentiate antitumor responses.

NCT04005365 aims at incorporating propranolol into neoad-

juvant chemotherapy in gastric cancer patients with the aim to

improve overall response. NCT02641314 aims at administering

a combination of propranolol with NSAID (celecoxib) anti-

neuroblastic drugs (cyclophosphamide, etoposide and vinblas-

tine) in children and adolescents with recurrent or progressive

neuroblastoma. The primary objective is to demonstrate the

non-inferiority in survival compared with controls, while as

secondary outcomes safety, tolerance, and disease response

rate will be assessed. NCT03108300 aims at assessing overall

and progression-free survival in patients with metastatic soft

tissue sarcoma co-administered propranolol 40 mg twice daily

and doxorubicin. NCT02897986 is a dose escalation trial to

determine the maximal tolerated dose of vinorelbine adminis-

tered in combination with daily oral propranolol in children

and teenagers with refractory solid tumors. NCT04682158

aims to determine the safety and efficacy of propranolol com-

bined with standard neoadjuvant chemoradiation, as well as an

impact on overall survival and pathologic response rate in

patients undergoing esophageal cancer resection. The rando-

mized phase II clinical trial NCT04493489 focuses on safety

and efficacy of propranolol in adjuvant BCG therapy after the

transurethral resection of bladder cancer and evaluates the

capacity of the combination treatment to decrease relapses

over a 2-year period. Table 6

Figure 2. Scheme of the biological eﬀects of β-blockers. cAMP, cyclic adenosine monophosphate; COX-2, cyclooxygenase 2; EGFR, epithelial growth factor receptor; ER,

endoplasmic reticulum; IL, interleukin; MDSCs, myeloid-derived suppressor cells; MMP, matrix metalloproteinase; NK, natural killer; PKA, protein kinase A; TME, tumor

microenvironment; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor. Created with BioRender.com.

ONCOIMMUNOLOGY 11

Table 3. Published observational studies (prospective, retrospective, and meta-analyses) investigating the inhibition of adrenergic signaling pathway in cancer patients.

Cancer Beta-blockers Conventional anticancer agents Results Study Ref.

Brain cancer β-blockers NA 225 patients included. Control of tumor growth (p=0.001), tumor progression (p=0.0001) and higher survival

(p=0.015). Strong correlation between β-blockers and survival (p=0.049)

Retrospective

150

Breast cancer (HER2+) Atenolol, bisoprolol,

carvedilol,

propranolol

Trastuzumab PFS adjusted HR=2.21, 95%CI[1.56–3.12]; p<0.001

OS adjusted HR=2.46, 95% CI[1.69–3.57]; p<0.001

Retrospective

165

Breast cancer (HER2-) Atenolol, bisoprolol,

metoprolol,

propranolol

Docetaxel and/or ramucirumab Improved PFS (15.5 vs 8.3 months); p=0.038

No signiﬁcant diﬀerence in OS

Retrospective

151

Breast cancer Atenolol, bisoprolol,

propranolol, timolol

NA Reduction in metastasis (p=0.026), tumor recurrence (p=0.001) and longer disease-free interval (p=0.01). A 57%

reduction in risk of metastasis (HR=0.430; 95%CI[0.200–0.926], p=0.031). A 71% reduction in mortality after 10

years (HR=0.291; 95%CI[0.119–0.715]; p=0.007). No signiﬁcant diﬀerence in vascular invasion.

Retrospective

152

Breast cancer β-blockers NA 46 245 patients included. Survival HR=0.44; 95%CI[0.26–0.73] with I

=78%. DFS HR=0.71; 95%CI[0.19–1.03] Meta-analysis

195

Colo-rectal cancer β-blockers Chemotherapy (2628 patients)

Radiotherapy (1427 patients)

4794 patients included. β-blockers decreased mortality (adjusted OR=0.88; 95%CI[0.77–1.00]; p=0.04) Retrospective

153

Hepato-cellular

carcinoma

Carvedilol, nadolol,

propranolol, timolol

NA 47 studies (28 RCT + 19 cohorts) included. No signiﬁcant association between propranolol (OR=0.94;95%CI [0.62–

1.44]) or timolol (OR=1.32; 95%CI [0.44–3.95]) and HCC incidence. Risk of HCC decreased by 26% and 38% with

nadolol (OR=0.74; 95%CI[0.64–0.86]; p=0.796) and carvedilol (OR=0.62; 95%CI[0.52–0.74]; p=0.776).

Meta-analysis

154

Hepato-cellular

carcinoma

Carvedilol, propranolol,

nadolol, timolol

NA 23 studies were included (totaling 2618 patients). β-blockers do not reduce mortality. Meta-analysis

196

Lung cancer Landiolol Adjuvant chemotherapy (8

patients)

28 patients included in the landiolol group and 29 in the control group. HR for RFS in the landiolol group was 0.41;

95%CI[0.13–1.34]; p = 0.1294.

HR for RFS in the landiolol group without adjuvant chemotherapy was 0.50; 95%CI[0.15–1.62];

p = 0.2363.

Retrospective

197

Lung cancer Selective agents:

atenolol,

bisoprolol,

metoprolol

Non selective agents:

carvedilol,

labetolol, nadolol,

propranolol, sotalol

Radiotherapy (100% patients)

Chemotherapy (90% patients)

722 patients (155 patients received β-blockers). Univariate analysis: better Distant Metastasis Free Survival

(p<0.01), DFS (p<0.01), and OS (p=0.01) compared with no β-blockers. Multivariate analysis: better DMFS

(HR=0.67; p=0.01), DFS (HR=0.74; p=0.02), and OS (HR=0.78; p=0.02)

Retrospective

155

Melanoma β-blockers NA 121 patients (30 patients treated with β-blockers). A 36% risk reduction of progression each year in the treated

group (95%CI[11%-54%]; p=0.002)

Retrospective

156

Melanoma Selective agents:

acebutolol, atenolol,

betaxolol,

bisoprolol,

celiprolol, esmolol,

metoprolol,

nebivolol

Non-selective

agents:

carteolol, carvedilol,

labetatol,

levobunolol,

metipranolol,

nadolol, oxprenolol,

penbutolol,

pindolol, practolol,

propranolol, sotalol,

timolol

± pembrolizumab No prognostic eﬀect of β-blockers on RFS (HR=0.67; 95%CI [0.38–1.19] in the pembrolizumab group and HR=1.15;

95%CI [0.80–1.66] in the placebo group).

Retrospective

164

(Continued)

12 K. CARNET LE PROVOST ET AL.

Table 3. (Continued).

Cancer Beta-blockers Conventional anticancer agents Results Study Ref.

Ovary cancer Atenolol, bisoprolol,

metoprolol,

oxprenolol, pindolol,

propranolol

NA Extension of at least 8 years post-surgery if use non selective β-blockers Retrospective

157

Ovary cancer Metoprolol No chemotherapy (9 patients)

IV platinum (146 patients)

IV-IP platinum (30 patients)

Metoprolol given before and during cytoreduction for 70 patients vs 115 patients (control group). OS was

signiﬁcantly higher in β-blocker group (44.2 vs 39.3 months; p=0.01). In multivariate analysis, β-blocker was

associated with signiﬁcant improvement in OS (HR 0.68; 95%CI[0.46–0.99]; p=0.046).

Retrospective

158

Ovary cancer Acebutolol, atenolol,

betaxolol,

bisoprolol,

metoprolol,

nebivolol,

penbutolol,

propranolol,

talinolol, soltalol

carboplatin, gemcitabine No diﬀerence in PFS (7.79 vs 7.62 months; p=0.95) and OS (21.2 vs 17.3 months; p=0.18) between β-blockers

group and control group.

Retrospective

163

Prostate cancer β-blockers No hormono- radio- or

chemotherapy prior surgery

(exclusion criteria)

11 117 men were included. β-blockers at time of surgery were signiﬁcantly associated with a lower risk of

treatment for cancer recurrence (adjusted HR=0.64; 95% CI[0.42–0.96]; p=0.03)

Prospective

159

Solid tumors Atenolol, bisoprolol,

carvedilol, labetalol,

metoprolol,

nebivolol, solatol

Immunotherapy (PD-1, PD-L1,

CTLA-4 inhibitors)

± chemotherapy

11 studies included (=10 156 patients). No association between β-blockers and OS (HR=0.97; 95%CI[0.85–1.11]) or

PFS (HR=0.98; 95%CI[0.90–1.06]). Signiﬁcant better response to immunotherapy in the cohort (OR=0.42; 95%CI

[0.19–0.94]; p=0.036) and lung cancer subgroup (OR= 0.25; 95%CI [0.08–0.83]); p=0.024)

Meta-analysis

162

Solid tumors Acebutolol, atenolol,

bisoprolol,

carvedilol, celiprolol,

labetolol,

metoprolol, nadolol,

nebivolol,

oxprenolol, pindolol,

propranolol, timolol

NA Reduction in risk of cancer (HR=0.33 95%CI[0.13; 0.83]; p=0.019). In the meta-analysis sub-analysis: lower risk of

cancer (MH-OR=0.93 95%CI[0.86; 1.01]; p=0.070).

Observational

and meta-

analysis

160

Solid tumors β-blockers Chemotherapy and radiotherapy in

some studies

20 cohorts and 4 case controls (76 538 patients). β-blockers were given after the diagnosis of cancer. HR all causes

mortality=0.89 (95%CI [0.81–0.98]). HR cancer mortality=0.89 (95%CI [0.79–0.99]).

Meta-analysis

161

Solid tumors β-blockers Immunotherapy (PD-1, PD-L1,

CTLA-4 inhibitors)

13 studies included (=3 331 patients). Concomitant use of NSAIDs, β-blockers and metformin is not associated

with improved OS or PFS.

Meta-analysis

198

Abbreviations: CI, conﬁdence interval; DMFS, distant metastasis free survival; HR, hazard ratio; IV, intravenous; IP, intraperitoneal; NSAIDs, non-steroidal anti-inﬂammatory drugs; OS, overall survival; PFS, progression free-survival;

RFS, recurrence free-survival.

ONCOIMMUNOLOGY 13

Table 4. Published interventional and randomized controlled trials investigating the inhibition of adrenergic signaling pathway in cancer patients.

Cancer Beta-blockers

Conventional anticancer

treatment Results Cardiovascular eﬀects Study Phase Ref.

Breast cancer (HER2+) Propranolol Neoadjuvant chemotherapy

(taxanes/ anthracyclines)

10 patients included. Propranolol started at 20mg and then increased to

80mg daily. Feasibility of combining propranolol with chemotherapy.

Bradycardia in 3 patients Interventional II

170

Breast cancer Propranolol No neoadjuvant chemotherapy

(exclusion criteria)

60 patients randomized to receive placebo or propranolol (escalating

doses 80-160mg daily for 7 days before surgery). Reduction in

intratumoral mesenchymal polarization and increase in immune cell

inﬁltration.

Minimal reduction in blood

pressure (<20 mmHg)

and heart rate (<10

mmHg)

Bradycardia in 1 patient

Hypotension in 3 patients

RCT II

168

Breast cancer Propranolol + etodolac NA 38 patients randomized to receive propranolol + etodolac 5 days before

and 6 days after surgery or placebo. Signiﬁcant decrease in epithelial

to mesenchymal transition, prometastatic/proinﬂammatory

transcription factors and tumor-inﬁltrating monocytes. Increase in

tumor-inﬁltrating B cells. Abrogation of serum IL-6 and C-reactive

protein levels, and IL-12/IFNγ production.

NA RCT II

172

Breast cancer Propranolol With or without parecoxib

No neoadjuvant chemo- or

radiotherapy (exclusion

criteria)

101 women were randomized to receive propranolol ± parecoxib or

placebo before and after mastectomy. β-blockers reduced surgical

stress-induced Treg cells. No additive or synergic eﬀect with

parecoxib.

Propranolol group:

signiﬁcant decrease in

heart rate during the per-

operative period

RCT NA

173

Colo-rectal cancer Propranolol + etodolac NA 34 patients included to receive propranolol + etodolac for 5 days before

and 15 days after surgery or placebo. Signiﬁcant improvement

(p<0.05) of tumor molecular markers. In compliant patients group,

recurrence rates were 0% in the treatment group and 29.4% in the

placebo group (p=0.054).

NA RCT II

174

Melanoma Propranolol Pembrolizumab 9 patients included in three groups (10 mg, 20 mg or 30 mg propranolol

twice a day). Association with immunotherapy was safe, tolerable,

increased IFN-γ and decreased IL-6.

10 mg group: 2 partial responses and 1 stable disease

20 mg group: 2 partial responses and 1 progressive disease

30 mg group: 3 partial responses

Hypotension in 1 patient

(30 mg)

Interventional I

171

Melanoma Propranolol NA 53 patients included (19 received propranolol). β-blockers are associated

with a 80% risk reduction in recurrence (HR=0.18; 95%CI [0.04–0.89];

p=0.03).

Propranolol group 15.8% disease progression and 10.5% death vs

41.2% and 17.7% in the control group.

DFS 89% propranolol group vs 64% at 3 years, p=0.04). Cox model : HR

DFS 0.18, 95%CI [0.04–0.89], p=0.03; HR OS 0.64, 95%CI [0.1–3.96],

p=0.63

NA RCT NA

169

Multiple myeloma Propanolol Melphalan 25 patients included. Feasibility to recruit and treat multiple myeloma

during hematopoietic cell transplantation.

Hypotension in 1 patient RCT II

166

Ovary cancer Propranolol Carboplatin and paclitaxel 26 patients included. Feasibility of propranolol before chemotherapy or

surgery. Decrease in adrenergic stress markers.

55.5% complete response/33.3% partial response/5.6% stable

response/5.6% progressive response

NA Interventional I

167

Abbreviations: DFS, disease free-survival; HR, hazard ratio; IFN, interferon; IL, interleukin; RCT, randomized controlled trial.

14 K. CARNET LE PROVOST ET AL.

Table 5. Completed and terminated clinical trials investigating the inhibition of adrenergic signaling pathway in cancer patients (not yet published).

Cancer Drug Assessed outcomes Status Phase Co-therapy Study NCT

Breast cancer Esmolol Metoprolol –Postoperative consumption of narcotic

–Impact of postoperative acute and chronic pain

–Nausea, vomiting

–Recurrence

Completed NA As a single agent RCT NCT01544959

Breast cancer Propanolol –Decrease in tumor proliferative index (Ki-67) Terminated II As a single agent Interventional NCT02596867

Breast cancer Propranolol –Number of patients with pathologic complete response at 6 months Completed II Combined with neoadjuvant

chemotherapy

Interventional NCT01847001

Gliobla-stoma Carvedilol –Correlation between RT-qPCR assay for circulating tumor cells and the

change in response to MRI results

–Evaluate response

Terminated Early phase I Combined with standard

chemotherapy

Interventional NCT03861598

Ovary cancer Propanolol –Feasibility of concurrent β–blocker administration with chemotherapy

–DFS

–Blood markers

–Immunohistochemistry of angiogenic markers on tumor samples

Completed I Concurrent chemotherapy Interventional NCT01308944

Ovary cancer Propanolol –Complete 6 cycles of chemotherapy

–Change in mood state

–DFS and OS

–Change in immune response

(IL-6, IL-8, VEGF)

Completed Early phase I Combined with chemotherapy Interventional NCT01504126

Prostate cancer Propanolol –Change in PSA

–Pain

–Time to symptom progression

–Change in correlative biomarkers

Terminated II Combined with etodolac RCT NCT01857817

Solid tumors Propanolol –Toxicity

–Change in VEGF

–Eﬀect of β-adrenergic blockade on the TME and on the host immune

system

–DFS and OS

Completed Early Phase I As a single agent Interventional NCT02013492

Abbreviations: CRS, cytokine release syndrome; DFS, disease-free-survival; IL, Interleukin; MRI, magnetic resonance imaging; ORR, overall response rate; OS, overall survival; PSA, prostate speciﬁc antigen; RCT, randomized

controlled trial; TME, tumor microenvironment; VEGF, Vascular Endothelial Growth Factor.

ONCOIMMUNOLOGY 15

Table 6. Ongoing clinical trials investigating the inhibition of adrenergic signaling pathway in cancer patients.

Cancer Drug Outcomes Status Phase Co-therapy Study NCT

Angio-sarcoma Propanolol –Clinical and histological

response (decrease of >30%

of Ki-67 index)

Recruiting II As a single agent Interventional NCT04518124

Bladder Propanolol –Two-year recurrence-free

survival

Not yet recruiting II Combined with BCG vaccine RCT NCT04493489

Breast Propanolol –Cytotoxic activity of NK cells,

levels of NKT cells,

lymphocytes, monocytes

and granulocytes; cytokine

levels; In vitro cytokine

secretion; levels of cortisol

and VEGF.

−5-year recurrence

Unknown NA Combined with etodolac during

perioperative period

RCT NCT00502684

Colo-rectal Propanolol −5-year DFS

–Tumor-inﬁltrating leucocytes.

Pro-tumor and

inﬂammatory cytokines

–Adverse eﬀects (Clavien-

Dindo classiﬁcation,

depression, anxiety, global

distress, fatigue)

Recruiting II Combined with etodolac during

perioperative period

RCT NCT03919461

Colo-rectal Propanolol –Recurrence

–Magnitude and duration of

surgically induced immune

depression

–Morbidity. Mortality

Unknown III Combined with etodolac during

perioperative period

RCT NCT00888797

Esophagus Propanolol −5-year DFS and OS. Recruiting II Combined with chemoradiation RCT NCT04682158

Gastro-esophagus Propanolol –Toxicities and adverse events

–DFS. ORR. OS.

Not yet recruiting II Combined with pembrolizumab,

ﬂuorouracil, oxaliplatin and

leucovorin

Interventional NCT05651594

Gastric Propanolol –ORR Unknown II Combined with neochemo-therapy Interventional NCT04005365

Gastro-intestinal Propanolol –Tumor size (Computed

tomography and Ki-67)

Unknown Early phase I As a single agent Interventional NCT03245554

Liver Propanolol –Failure free survival

–Clinical beneﬁt response

Unknown II Combined with etodolac and sorafenib RCT NCT01265576

Liver, pancreas, gallbladder Propanolol –Eﬃcacy in boosting the

eﬀects of immunotherapy

–Feasibility. Safety

–Tolerability

–DFS. OS

Not yet recruiting II Combined with durvalumab,

gemcitabine, paclitaxel,

tremelimumab, cisplatin

Interventional NCT05451043

Lung Landiolol −2-year relapse-free survival

and OS after surgery

–additional treatment after

recurrence. Safety events.

Postoperative complications

Unknown III As a single agent RCT No NCT

PMID31829248

Melanoma Propanolol –Dose limiting toxicities

–DFS. ORR. OS.

Recruiting I/II Combined with pembrolizumab Interventional NCT03384836

Melanoma Propanolol –DFS. OS. Mortality

–Long-term safety

Unknown II/III As a single agent RCT NCT02962947

Melanoma Propranolol –PFS. ORR. OS Not yet recruiting I Combined with ipilimumab and

nivolumab

Interventional NCT05968690

(Continued)

16 K. CARNET LE PROVOST ET AL.

Table 6. (Continued).

Cancer Drug Outcomes Status Phase Co-therapy Study NCT

Multiple myeloma Propanolol –Changes in immune cell

subsets

–Changes in the gut

microbiome

–Comparison in bone markers

–Changes in body composition

–Changes in stress, anxiety,

fatigue, functional status,

nutritional behavior before

and after intermittent

fasting and stress-related

biomarkers

Recruiting NA As a single agent Interventional NCT05312255

Neuro-blastoma Propanolol –Event free survival

–Disease control rate at 6 and

12 months

–OS

–Hospitalization days.

–Number of transfusion days

–Drop-out rate

Recruiting II Combined with celecoxib, cyclo-

phosphamide, vinblastine,

etoposide

Interventional NCT02641314

Pancreas β-blockers –DFS. OS. Recruiting NA As a single agent or combined with

aspirin, metformin, ACE-inhibitors,

statins

Observational

Prospective

NCT04245644

Pancreas Propanolol –Recurrence

–Tumor-inﬁltrating leukocytes.

Protumor and inﬂammatory

cytokines

–Adverse eﬀects (Clavien-

Dindo classiﬁcation,

depression, anxiety, global

distress, fatigue)

Recruiting II Combined with etodolac RCT NCT03838029

Prostate Carvedilol –Change in biomarkers (Ki-67,

TUNEL assay) in prostate

biopsy

–Change in serum PSA

Not yet recruiting II As a single agent prior to surgery Interventional NCT02944201

Prostate Propanolol –Feasibility

–Safety and tolerability

–Bioavailability

–Changes in catecholamines

levels in perioperative

period. Serum level of PSA

–Change in distress

–Surgical complications

Proportion of patients

requiring vasopressors.

Procedure time. Blood loss.

–Tumor-inﬁltrating leucocytes.

–Prognostic and predictive

markers

Recruiting II As a single agent RCT NCT05679193

Sarcoma Propanolol –DFS. OS Unknown II Combined with doxorubicin Interventional NCT03108300

Solid tumors

Hematolo-gical malignancy

Metoprolol –Safety and tolerability

–Eﬃcacy for CRS control and

precaution

Recruiting I/II Combined with CAR-T cells therapy ±

inﬂiximab, etanercept, tocilizumab

and/or other agents

Interventional NCT04082910

(Continued)

ONCOIMMUNOLOGY 17

Table 6. (Continued).

Cancer Drug Outcomes Status Phase Co-therapy Study NCT

Solid tumors Propanolol –Decrease in toxicity of

chemotherapy

Unknown I Combined with vinorelbine Interventional NCT02897986

Urothelial Propanolol –DFS. ORR. OS.

–Adverse events

Recruiting II Combined with pembrolizumab Interventional NCT04848519

Abbreviations: ACE, angiotensin-converting enzyme; BCG, Bacillus Calmette-Guérin; CAR-T cells, chimeric antigenic receptor-T cells; CRS, cytokine release syndrome; DFS, disease-free survival; NK, natural killer; ORR, overall

response rate; OS, overall survival; PFS, progression free survival; PSA, prostate speciﬁc antigen; RCT, randomized controlled trial; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.

18 K. CARNET LE PROVOST ET AL.

β-blockers combined with immunotherapy

Five interventional trials (NCT05651594, NCT05451043,

NCT03384836, NCT04848519, NCT01265576, NCT05968690)

aim at exploring the addition of β-AR antagonists to immu-

notherapy (with pembrolizumab, durvalumab, tremelimumab,

ipilimumab or nivolumab) alone or together with standard

chemotherapy in the treatment of unresectable advanced and/

or metastatic digestive adenocarcinoma, stage III/IV melanoma

and urothelial cancers. The primary objective is to evaluate the

efficacy of β-blockade in boosting immunotherapy as measured

by response evaluation criteria in solid tumors (RECIST).

Secondary explorative objectives encompass correlations of bio-

markers (such as immune effectors, circulating cytokines and

stress) with efficacy, progression-free survival and overall

survival.

NCT04082910 will test the β1 adrenergic receptor blocker

metropolol for its ability to control and prevent of cytokine

release syndrome (CRS) in patients with lymphoma and leu-

kemia enrolled for chimeric antigen receptor (CAR)-T cell

infusion. Safety and tolerability of metropolol will be con-

firmed by evaluating heart rate and blood pressure, while the

efficacy in the control of CRS will be assessed by monitoring

body temperature and serum IL-6 levels.

β-blockers combined with other agents

Four prospective trials (NCT00502684, NCT03919461,

NCT00888797, NCT03838029) aim at combining β-blockers

with COX-2 inhibitors before, during, and after breast or

colorectal cancer surgery to evaluate the impact on immune

effector activity and tumor-infiltrating leucocytes. Moreover,

cytokine secretion and serum levels of cortisol and VEGF will

be assessed alongside psychological examinations. Oncological

outcomes such as morbidity and mortality will be assessed in

a 5-year follow up. Lastly, the monocentric observational pro-

spective study NCT04245644 will evaluate if the combination

of β-blockers with four chemopreventive agents (angiotensin

converting enzyme inhibitors, aspirin, metformin, and statin)

can improve the overall and disease-free survival in 800

patients with pancreatic ductal adenocarcinoma.

Discussion

Stress-related hormones and signaling via β-adrenergic recep-

tors impact oncogenesis. Preclinical researches and pilot clinical

trials support the hypothesis that β-blockers administered at

clinically relevant concentrations during anticancer therapy

extend the lifespan of individuals with malignant disease.

Whether this effect is due to the direct blockage of β-AR and/

or due to an indirect systemic effect via the reduction of stress

and corticotropic activity is still under discussion. Indeed, upon

physical, biological, and psychological stress, the corticotropic

HPA axis is activated releasing substantial amounts of immu-

nosuppressive catecholamines and cortisol. Catecholamines are

ligands of β-AR located at the plasma membrane of cytolytic

immune effectors, negatively impacting mobility and activity,

but also on β-AR present on cancer cells where they can stimu-

late proliferation, invasion, and migration. Of note, different β-

AR subtypes are present with a strong predominance of the β2

sub-group.

ICI 118 551, the most selective β2-AR antagonist,

demonstrated consistent antitumor activity while no or partial

effects were observed with the β1-specific blocker atenolol.

41,105

The implication of β1-receptors is still uncertain, and further

investigation is required to understand the contribution of each

type of receptor in tumor development. Selective β3-AR antago-

nists have been even less studied, however, preclinical data

noticed antiproliferative and apoptotic effects, suggesting

β3-AR could be a target for anticancer therapy.

At present, in the field of oncology, preference is giving

to nonspecific β-blockers such as propranolol, which tar-

gets both β1/2 ARs. However, it is important to consider

potential side effects arising from dual β1/2 blocking. Due

to the expression of β-ARs at the tumor cell surface, some

research has explored the use of carvedilol, a α-blocker,

with alpha-blocking property and has demonstrated an

anti-tumor effect. Thus, reduced tumor cell proliferation

was observed following the use of α2-AR agonists such as

clonidine, a common anti-hypertensive agent.

176

This

might indicate a crosstalk between α2- and β2-ARs in

stimulating cancer cell growth. Further research is needed

to elucidate the pro- or anti-tumor profiles of α-ARs.

An interesting aspect was advanced with clinical trial

NCT01544959 in which authors hypothesized that fentanyl,

an opioid used to control acute pain during induction and

maintenance of anesthesia, could be replaced by β-blockers.

Opioids have been ascribed with pro-tumorigenic effects, such

as stimulating tumor cell migration by the activation of MMPs,

activation of the oncogene c-MYC and inhibition of anti-

angiogenic TSP-1.

177–179

Alternative techniques such as

“opioid-free-anesthesia”, a specific protocol mixing local anes-

thetics, ketamine, magnesium and dexmedetomidine, are

emerging for the management of acute pain during the per-

operative period. In this setting, due to their anti-tumor effect

and immunostimulatory properties, β-blockers appear as an

appealing option for opioid replacement. Reportedly, β-adre-

nergic stimulation inhibits the primary phase of CD8

T lymphocytes activation, thus providing a rationale for the

administration of β-blockers together with T cell targeted

immunotherapies.

122

Surgical glucocorticoid stress is significantly activated by

local and systemic inflammatory pain that can be caused by

surgical tissue damage and is mediated by pro-tumorigenic

COX-2. Several randomized controlled trials advanced the

possibility to potentiate antitumor effects by blocking sympa-

thetic signaling and managing pain with a combination of β-

AR antagonists and COX-2 inhibitors (NCT00502584;

NCT03919461; NCT00888797; NCT03838029). COX-2 inhibi-

tors belong to the family of non-steroidal anti-inflammatory

drugs (NSAIDs) and previous observational clinical trials sup-

ported the notion that NSAIDs might improve oncological

outcomes. Thus, Desmedt et al. observed that intraoperative

ONCOIMMUNOLOGY 19

administration of ketorolac, a COX-1 and COX-2 inhibitor,

significantly reduced the incidence of distant recurrences after

breast cancer surgery.

180

In a study involving 327 women

undergoing mastectomy, Forget et al. reported a significantly

lower recurrence rate (p = 0.019) after administration of ketor-

olac prior to surgery, while other analgesics, such as sufentanil,

ketamine and clonidine, showed no effect.

181

A retrospective

analysis in a cohort of 720 breast cancer patients revealed that

injection of the NSAIDs ketorolac and diclofenac during con-

servative breast cancer surgery correlated with improved dis-

ease-free (HR = 0.57, p = 0.01) and overall survival (HR = 0.35,

p = 0.03).

182

Finally, in a propensity score matching study

involving 2502 patients with non-small cell lung cancer, immu-

notherapy combined with the administration of NSAIDs was

associated with a better overall survival (HR = 0.85,

p < 0.001).

183

In vitro, ketorolac was found to decrease prolif-

eration, migration and angiogenesis, and to enhance the sensi-

tivity of renal cancer to apoptosis. In mice, ketorolac caused

tumor growth inhibition when used as a standalone agent or

combined with sunitinib.

184

In a model of head and neck

squamous cell carcinoma, COX-2 inhibition showed additive

and synergistic effects with EGFR inhibitors enhancing tumor

cell death both in vitro and in vivo, especially in PIK3CA-

mutated cancers.

Altogether, the combination of COX-2

inhibitors with β-blockers seems to be a promising option to

potentiate antitumor responses.

In addition, activation of β-ARs in response to surgical

stress promotes the survival of circulating tumor cells and

increases the incidence of metastases. Surgical glucocorti-

coid stress can be optimally managed by spinal anesthesia

or epidural anesthesia during the perioperative period.

185

By controlling stress and inflammatory pain, medullar

anesthesia also positively impacted oncological outcome

by decreasing the incidence of recurrence. However, these

analgesic procedures are contraindicated in bleeding disor-

ders, infection, backbone osteosynthesis or upon patient

refusal, necessitating alternative analgesia techniques. In

this case, anxiolytic premedication (the day before and 2 h

before surgery), for instance with benzodiazepines, can

control surgical stress. Premedication has four main objec-

tives: i) decreasing the level of anxiety and its physical

consequences such as tachycardia, perspiration and poly-

pnea; ii) minimizing the intensity of biochemical reactions

and metabolic activity; iii) enhancing the analgesic potency

of anesthetics; and iv) blocking parasympathetic effects

induced by anesthesia and surgery such as salivary hyper-

secretion, nausea, vomiting, laryngeal spasms, and dys-

rhythmia. Here, β-blockers offer an appealing

premedication option because they address all the afore-

mentioned objectives without the known side effects of

benzodiazepines such as sleepiness, confusion, and balance

disorder. In contrast to other cardiologic agents targeting

the angiotensin system, β-blockers are not contraindicated

prior to anesthetic procedures. To reverse or inhibit the

surgical glucocorticoid stress-induced immune system sup-

pression, β-blockers used at a dose not triggering hypoten-

sion, could be considered for cancer patients, especially in

the case of contraindication for medullar anesthesia. So far,

specific guidelines for the use of β-blockers during the

preoperative period are still lacking, and the efficacy of

such premedications still requires further demonstration.

Conclusion

All forms of stress, be they physical, biological, or of psycho-

logical origin, can activate sympathetic signaling pathways

promoting the release of catecholamines and other stress med-

iators into the systemic circulation. Catecholamines promote

the proliferation, migration, and invasion of tumor cells, while

suppressing the cytolytic function of immune effectors,

through direct interaction with β-AR located on their plasma

membrane. β-blockers can counteract such deleterious effects

by competitively interfering with the binding of catechola-

mines to AR. Promising results from preclinical and clinical

pilot studies suggesting that β-blockade can improve the out-

come of cancer treatments now await confirmation in ongoing

prospective randomized controlled trials. The facts that

β-blockers are already approved and widely used for cardio-

vascular indications may accelerate their deployment in onco-

logical practice.

Abbreviations

AA arachidonic acid

ACE angiotensin-converting enzyme

ACTH adrenocorticotropic hormone

AP-1 activator protein 1

AR adrenergic receptor

BCG Bacillus Calmette-Guérin

cAMP cyclic adenosine monophosphate

CAR-T cells chimeric antigenic receptor-T cells

ccRCC clear cell Renal Cell Carcinoma

CDDP cisplatin

CI confidence interval

COX-2 cyclooxygenase 2

CREB cAMP response element-binding protein

CRS cytokine release syndrome

CTLA4 cytotoxic T-lymphocyte-associated protein 4

CTLs cytotoxic T lymphocytes

DC dendritic cell

DFS disease-free survival

EGF epidermal growth factor

EGFR epithelial growth factor receptor

ER endoplasmic reticulum

ERK extracellular signal-regulated kinase

5-FU 5-fluorouracil

HPA hypothalamic-pituitary-adrenal

HR Hazard ratio

HPA hypothalamic-pituitary-adrenal

IFN interferon

IL interleukin

MAPK mitogen activated protein kinase

MDSCs myeloid-derived suppressor cells

MMP matrix metalloproteinase

NFkB nuclear factor kappa B

20 K. CARNET LE PROVOST ET AL.

NK natural killer

NSAIDs non-steroidal anti-inflammatory drugs

ORR overall response rate

OS overall survival

OSCC oral squamous cell carcinoma

PD-1 programmed death receptor 1

PFS progression-free survival

PGE2 prostaglandin E2

PKA/C protein kinase A/C

PSA prostate-specific antigen

RCT randomized controlled trial

RFS recurrence-free survival

ROS reactive oxygen species

TME tumor microenvironment

TUNEL terminal deoxynucleotidyl transferase dUTP

nick end labeling

VEGF vascular endothelial growth factor

VHL Von Hippel Lindau

Acknowledgments

KCLP receives funding from the Agence Régionale de Santé (ARS) Ile-

de-France (Année-recherche Pharmacie). OK receives funding from

Institut National du Cancer (INCa) and Agence Nationale de la

Recherche (ANR); GK is supported by the Ligue contre le Cancer

(équipe labellisée); ANR – Projets blancs; AMMICa US23/CNRS

UMS3655; Association pour la recherche sur le cancer (ARC);

Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale

(FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European

Joint Programme on Rare Diseases (EJPRD); European Research

Council (ICD-Cancer), European Union Horizon 2020 Projects

Oncobiome and Crimson; Fondation Carrefour; INCa; Institut

Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-

0001); a Cancer Research ASPIRE Award from the Mark

Foundation; the RHU Immunolife; Seerave Foundation; SIRIC

Stratified Oncology Cell DNA Repair and Tumor Immune

Elimination (SOCRATE); and SIRIC Cancer Research and

Personalized Medicine (CARPEM). This study contributes to the

IdEx Université de Paris ANR-18-IDEX-0001.

Disclosures statement

OK and GK have been holding research contracts with Daiichi Sankyo,

Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics,

Samsara Therapeutics, Sanofi, Tollys, and Vascage. GK is on the Board

of Directors of the Bristol Myers Squibb Foundation France. GK is

a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara

Therapeutics and Therafast Bio. OK is a scientific co-founder of Samsara

Therapeutics. GK is in the scientific advisory boards of Hevolution,

Institut Servier and Longevity Vision Funds. GK is the inventor of patents

covering therapeutic targeting of aging, cancer, cystic fibrosis and meta-

bolic disorders. GK’s brother, Romano Kroemer, was an employee of

Sanofi and now consults for Boehringer-Ingelheim. GK’wife, Laurence

Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte,

Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus,

Transgene, 9 m, Tusk and Roche, was on the on the Board of Directors

of Transgene, is a cofounder of everImmune, and holds patents covering

the treatment of cancer and the therapeutic manipulation of the micro-

biota. The funders had no role in the design of the study; in the writing of

the manuscript, or in the decision to publish the results. The other authors

declare no conflicts of interest.

Funding

The author(s) reported there is no funding associated with the work

featured in this article.

ORCID

Lucillia Bezu http://orcid.org/0000-0002-3569-6066

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28 K. CARNET LE PROVOST ET AL.

Trial watch: dexmedetomidine in cancer therapy

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Mar 2024

Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist that is widely used in intensive and anesthetic care for its sedative and anxiolytic properties. DEX has the capacity to alleviate inflammatory pain while limiting immunosuppressive glucocorticoid stress during major surgery, thus harboring therapeutic benefits for oncological procedures. Recently, the molecular mechanisms of DEX-mediated anticancer effects have been partially deciphered. Together with additional preclinical data, these mechanistic insights support the hypothesis that DEX-induced therapeutic benefits are mediated via the stimulation of adaptive anti-tumor immune responses. Similarly, published clinical trials including ancillary studies described an immunostimulatory role of DEX during the perioperative period of cancer surgery. The impact of DEX on long-term patient survival remains elusive. Nevertheless, DEX-mediated immunostimulation offers an interesting therapeutic option for onco-anesthesia. Our present review comprehensively summarizes data from preclinical and clinical studies as well as from ongoing trials with a distinct focus on the role of DEX in overcoming (tumor microenvironment (TME)-imposed) cancer therapy resistance. The objective of this update is to guide clinicians in their choice toward immunostimulatory onco-anesthetic agents that have the capacity to improve disease outcome.

The place of beta-adrenergic receptor blockers in the treatment of arterial hypertension: from bench-to-bedside

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Jun 2024
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Perioperative Immunosuppressive Factors during Cancer Surgery: An Updated Review

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Jun 2024

Surgical excision of the primary tumor represents the most frequent and curative procedure for solid malignancies. Compelling evidence suggests that, despite its beneficial effects, surgery may impair immunosurveillance by triggering an immunosuppressive inflammatory stress response and favor recurrence by stimulating minimal residual disease. In addition, many factors interfere with the immune effectors before and after cancer procedures, such as malnutrition, anemia, or subsequent transfusion. Thus, the perioperative period plays a key role in determining oncological outcomes and represents a short phase to circumvent anesthetic and surgical deleterious factors by supporting the immune system through the use of synergistic pharmacological and non-pharmacological approaches. In line with this, accumulating studies indicate that anesthetic agents could drive both protumor or antitumor signaling pathways during or after cancer surgery. While preclinical investigations focusing on anesthetics’ impact on the behavior of cancer cells are quite convincing, limited clinical trials studying the consequences on survival and recurrences remain inconclusive. Herein, we highlight the main factors occurring during the perioperative period of cancer surgery and their potential impact on immunomodulation and cancer progression. We also discuss patient management prior to and during surgery, taking into consideration the latest advances in the literature.

Anticancer effect of propranolol on diethylnitrosamine‐induced hepatocellular carcinoma rat model

Article

Feb 2024

Background Hepatocellular carcinoma (HCC) is the most widespread type of primary liver cancer. Diethylnitrosamine (DEN), a hepatotoxic hepatocarcinogenic compound, is used to induce HCC in animal models. The non‐selective β‐blocker propranolol demonstrated antiproliferative activity in many cancer types. Objective This investigation aimed to evaluate the anticancer effect of propranolol against DEN‐induced HCC in rats. Methods Thirty adult male rats were divided into the following groups: Group I (C, control), Group II (HCC); received DEN, 70 mg/kg body weight (b.wt.) once a week for 10 weeks, to induce HCC, and Group III (HCC/Prop); received DEN for 10 weeks for HCC induction, then received 20 mg/kg b.wt. propranolol, intraperitoneally for four successive weeks. Results HCC was developed in rats' livers and confirmed via significant liver architecture changes, significantly elevated activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), α‐fetoprotein (AFP), total‐ and direct‐bilirubin (Bil), and a decline in albumin (ALB) level in serum. HCC group demonstrated elevated levels of malondialdehyde (MDA), nitric oxide (NO), HIF‐1α, IL‐8, NF‐κB, PGE2, TGF‐β1, VEGF, and CD8, but significant decline of GSH, and IL‐10 level, with suppression of the antioxidant enzymes' activities. In addition, the gene expression of the hepatic inducible nitric oxide synthase (iNOS), and LAG‐3 were up‐regulated. Moreover, the protein expression of p‐PKC was up‐regulated, while that of PD‐1 and PD‐L1 were down‐regulated in the liver tissues of the HCC group. However, propranolol ameliorated the investigated parameters in the HCC/Prop group. Conclusion Propranolol exhibited an anticancer effect and thus can be considered as a promising treatment for HCC. Blocking of PD‐1/PD‐L1 and LAG‐3 signals participated in the anti‐tumor effect of propranolol on HCC.

The cancer-immune dialogue in the context of stress

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Oct 2023
NAT REV IMMUNOL

Although there is little direct evidence supporting that stress affects cancer incidence, it does influence the evolution, dissemination and therapeutic outcomes of neoplasia, as shown in human epidemiological analyses and mouse models. The experience of and response to physiological and psychological stressors can trigger neurological and endocrine alterations, which subsequently influence malignant (stem) cells, stromal cells and immune cells in the tumour microenvironment, as well as systemic factors in the tumour macroenvironment. Importantly, stress-induced neuroendocrine changes that can regulate immune responses have been gradually uncovered. Numerous stress-associated immunomodulatory molecules (SAIMs) can reshape natural or therapy-induced antitumour responses by engaging their corresponding receptors on immune cells. Moreover, stress can cause systemic or local metabolic reprogramming and change the composition of the gastrointestinal microbiota which can indirectly modulate antitumour immunity. Here, we explore the complex circuitries that link stress to perturbations in the cancer-immune dialogue and their implications for therapeutic approaches to cancer.

Non-selective beta-blockers and the incidence of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis

Article

Full-text available

Jul 2023

Background: Hepatocellular carcinoma (HCC) is a serious complication of cirrhosis. Currently, non-selective beta-blockers (NSBBs) are commonly used to treat portal hypertension in patients with cirrhosis. The latest research shows that NSBBs can induce apoptosis and S-phase arrest in liver cancer cells and inhibit the development of hepatic vascular endothelial cells, which may be effective in preventing HCC in cirrhosis patients. Aim: To determine the relationship between different NSBBs and HCC incidence in patients with cirrhosis. Methods: We searched the Cochrane database, MEDLINE, EMBASE, PubMed, and Web of Science. Cohort studies, case‒control studies, and randomized controlled trials were included if they involved cirrhosis patients who were divided into an experimental group using NSBBs and a control group with any intervention. Based on heterogeneity, we calculated odds ratio (OR) and 95% confidence interval (CI) using random-effect models. We also conducted subgroup analysis to explore the source of heterogeneity. Sensitivity analysis and publication bias detection were performed. Results: A total of 47 studies included 38 reporting HCC incidence, 26 reporting HCC-related mortality, and 39 reporting overall mortality. The HCC incidence between the experimental group and the control group was OR = 0.87 (0.69 and 1.10), p = 0.000, and I ² = 81.8%. There was no significant association between propranolol (OR = 0.94 and 95%CI 0.62–1.44) or timolol (OR = 1.32 and 95%CI 0.44–3.95) and HCC incidence, while the risk of HCC decreased by 26% and 38% with nadolol (OR = 0.74 and 95%CI 0.64–0.86) and carvedilol (OR = 0.62 and 95%CI 0.52–0.74), respectively. Conclusion: Different types of NSBB have different effects on the incidence of patients with cirrhosis of the liver, where nadolol and carvedilol can reduce the risk. Also, the effect of NSBBs may vary in ethnicity. Propranolol can reduce HCC incidence in Europe and America. Systematic Review Registration: identifier https://CRD42023434175 , https://www.crd.york.ac.uk/PROSPERO/ .

Survival outcomes of beta-blocker usage in HER2-positive advanced breast cancer patients: a retrospective cohort study

Article

Full-text available

Jun 2023

Background: Clinical trials investigating the effects of beta-blockers (BBs) on cancer are underway. Evidence from preclinical research suggests that BBs could serve as anticancer agents and immune boosters. There is conflicting evidence regarding the effect of BB use on clinical outcomes in patients with breast cancer. Objectives: The study aimed to determine whether BB use is associated with progression-free survival (PFS) and overall survival (OS) in patients receiving anti-human epidermal growth factor receptor 2 (HER2) treatment for advanced breast cancer. Design: Retrospective hospital-based study. Methods: The participants enrolled were breast cancer patients with advanced HER2-positive status who initiated trastuzumab monotherapy or concomitant therapy with trastuzumab and any dose of BB. The patients were enrolled between January 2012 and May 2021 and divided into three groups based on whether they received a BB or not in the therapeutic regimen: BB-/trastuzumab+, BB+ (non-selective)/trastuzumab+, and BB+ (selective)/trastuzumab+. PFS and OS were the primary and secondary endpoints, respectively. Results: The estimated median PFS in the BB-/trastuzumab+, BB+ (non-selective)/trastuzumab+, and BB+ (selective)/trastuzumab+ groups was 51.93, 21.50, and 20.77 months, respectively. The corresponding OS was 56.70, 29.10, and 27.17 months. The intergroup differences in these durations were significant. Both PFS [adjusted hazard ratio (HR): 2.21, 95% confidence interval (CI): 1.56-3.12; p < 0.001]) and OS (adjusted HR: 2.46, 95% CI: 1.69-3.57; p < 0.001) were worse when BBs were used. Conclusion: Our study provides important evidence that BB use potentially has a negative effect on patients with HER2-positive advanced breast cancer. Nevertheless, despite the study's results, cardiovascular disease (CVD) should be appropriately treated in patients with HER2-positive advanced breast cancer. Other types of drugs can be used to treat CVD, but BB use should be avoided. Large real-world database and prospective studies should be conducted to validate the results of this study.

Ketorolac modulates Rac-1/HIF-1α/DDX3/β-catenin signalling via a tumor suppressor prostate apoptosis response-4 (Par-4) in renal cell carcinoma

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Full-text available

Apr 2023

Renal cell carcinoma (RCC) is the most difficult-to-treat form of kidney cancer with a median 5-year survival of 10% under metastatic setting. In RCC, although cytoreductive nephrectomy is common, approximately 20–30% of patients will develop recurrent cancer after surgery, which highlights the need for an effective therapy. Rho-GTPases viz, Rac-1 and Cdc42 are the central regulators of cancer cell migration and invasion and thus metastasis in multiple cancer types. Hence, we elucidated the role of Ketorolac, a modulator Rho-GTPases against RCC through potentiation of tumor suppressor Par-4. The effect of Ketorolac alone and in combination on proliferation, apoptosis, cell-cycle progression, migration, tumor inhibition and their related markers were studied. Moreover, Ketorolac’s impact on metastasis by influencing Rac-1/HIF-1α/DDX3/β-catenin signalling was studied with respect to its ability to modulate the expression of tumor suppressor Par-4, and this mechanism was confirmed by siRNA knockdown studies. Ketorolac induced cytotoxicity in a panel of renal cells including patient derived tumor cells with IC50 2.8 to 9.02 mM and 0.28 to 3.8 mM in monolayer and anchorage independent clonogenic assays respectively. Ketorolac caused significant down regulation of proliferation (Ki-67, Cyclin D1, pRB and DDX3), migration/invasion (Rac-1, Cdc42, and Tiam1), and angiogenesis (HIF-1α and VEGF) markers as studied by gene and protein expression. Moreover, it caused a significant upregulation of tumor suppressor Par-4 known to be downregulated in RCC. This mechanism was further confirmed by using siRNA knockdown studies where we could demonstrate a negative relation between the expression of Par-4 and Rac-1/Cdc42. Importantly, Ketorolac alone and in combination with Sunitinib showed tumor growth inhibition (TGI) of 73% and 86% respectively in xenograft model. This anti-tumor activity was further corroborated by down regulation of Rac-1/Cdc42/HIF-1α/DDX3/β-catenin signalling. This is the first report which implicates the role of Ketorolac against RCC by acting as a small molecule secretagogue causing upregulation of Par-4 in autocrine and paracrine manner. Consequently, these findings suggest that Par-4 can serve as a valuable therapeutic target and a prognostic marker for the treatment of RCC.

Activation of β-Adrenoceptors Promotes Lipid Droplet Accumulation in MCF-7 Breast Cancer Cells via cAMP/PKA/EPAC Pathways

Article

Full-text available

Jan 2023
INT J MOL SCI

Physiologically, β-adrenoceptors are major regulators of lipid metabolism, which may be reflected in alterations in lipid droplet dynamics. β-adrenoceptors have also been shown to participate in breast cancer carcinogenesis. Since lipid droplets may be seen as a hallmark of cancer, the present study aimed to investigate the role of β-adrenoceptors in the regulation of lipid droplet dynamics in MCF-7 breast cancer cells. Cells were treated for up to 72 h with adrenaline (an endogenous adrenoceptor agonist), isoprenaline (a non-selective β-adrenoceptor agonist) and salbutamol (a selective β2-selective agonist), and their effects on lipid droplets were evaluated using Nile Red staining. Adrenaline or isoprenaline, but not salbutamol, caused a lipid-accumulating phenotype in the MCF-7 cells. These effects were significantly reduced by selective β1- and β3-antagonists (10 nM atenolol and 100 nM L-748,337, respectively), indicating a dependence on both β1- and β3-adrenoceptors. These effects were dependent on the cAMP signalling pathway, involving both protein kinase A (PKA) and cAMP-dependent guanine-nucleotide-exchange (EPAC) proteins: treatment with cAMP-elevating agents (forskolin or 8-Br-cAMP) induced lipid droplet accumulation, whereas either 1 µM H-89 or 1 µM ESI-09 (PKA or EPAC inhibitors, respectively) abrogated this effect. Taken together, the present results demonstrate the existence of a β-adrenoceptor-mediated regulation of lipid droplet dynamics in breast cancer cells, likely involving β1- and β3-adrenoceptors, revealing a new mechanism by which adrenergic stimulation may influence cancer cell metabolism.

Fibroblasts and macrophages cooperate to create a pro-tumorigenic and immune resistant environment via activation of TGF-β/IL-6 pathway in neuroblastoma

Article

Full-text available

Dec 2022

Tumor-associated macrophages (TAM) and cancer-associated fibroblasts (CAF) and their precursor mesenchymal stromal cells (MSC) are often detected together in tumors, but how they cooperate is not well understood. Here, we show that TAM and CAF are the most abundant nonmalignant cells and are present together in untreated human neuroblastoma (NB) tumors that are also poorly infiltrated with T and natural killer (NK) cells. We then show that MSC and CAF-MSC harvested from NB tumors protected human monocytes (MN) from spontaneous apoptosis in an interleukin (IL)-6 dependent mechanism. The interactions of MN and MSC with NB cells resulted in a significant induction or increase in the expression of several pro-tumorigenic cytokines/chemokines (TGF-β1, MCP-1, IL-6, IL-8, and IL-4) but not of anti-tumorigenic cytokines (TNF-α, IL-12) by MN or MSC, while also inducing cytokine expression in quiescent NB cells. We then identified a TGF-β1/IL-6 pathway where TGF-β1 stimulated the expression of IL-6 in NB cells and MSC, promoting TAM survival. Evidence for the contribution of TAM and MSC to the activation of this pathway was then provided in xenotransplanted NB tumors and patients with primary tumors by demonstrating a direct correlation between the presence of CAF and p-SMAD2 and p-STAT3. The data highlight a new mechanism of interaction between TAM and CAF supporting their pro-tumorigenic function in cancer.

Selective depletion of polymorphonuclear myeloid derived suppressor cells in tumor beds with near infrared photoimmunotherapy enhances host immune response

Article

Full-text available

Nov 2022

The immune system is recognized as an important factor in regulating the development, progression, and metastasis of cancer. Myeloid-derived suppressor cells (MDSCs) are a major immune-suppressive cell type by interfering with T cell activation, promoting effector T cell apoptosis, and inducing regulatory T cell expansion. Consequently, reducing or eliminating MDSCs has become a goal of some systemic immunotherapies. However, by systemically reducing MDSCs, unwanted side effects can occur. Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed treatment that selectively kills targeted cells without damaging adjacent normal cells. The aim of this study is to evaluate the antitumor efficacy of MDSC-directed NIR-PIT utilizing anti-Ly6G antibodies to specifically destroy polymorphonuclear (PMN)-MDSCs in the tumor microenvironment (TME) in syngeneic mouse models. PMN-MDSCs were selectively eliminated within tumors by Ly6G-targeted NIR-PIT. There was significant tumor growth suppression and prolonged survival in three treated tumor models. In the early phase after NIR-PIT, dendritic cell maturation/activation and CD8⁺ T cell activation were enhanced in both intratumoral tissues and tumor-draining lymph nodes, and NK cells demonstrated increased expression of cytotoxic molecules. Host immunity remained activated in the TME for at least one week after NIR-PIT. Abscopal effects in bilateral tumor models were observed. Furthermore, the combination of NIR-PIT targeting cancer cells and PMN-MDSCs yielded synergistic effects and demonstrated highly activated host tumor immunity. In conclusion, we demonstrated that selective local PMN-MDSCs depletion by NIR-PIT could be a promising new cancer immunotherapy.

Effects of Adrenergic Receptor Stimulation on Human Hemostasis: A Systematic Review

Article

Apr 2023
ADV EXP MED BIOL

Catecholamine stimulation over adrenergic receptors results in a state of hypercoagulability. Chronic stress involves the release and increase in circulation of catecholamines and other stress related hormones. Numerous observational studies in human have related stressful scenarios to several coagulation variables, but controlled stimulation with agonists or antagonists to adrenergic receptors are scarce. This systematic review is aimed at presenting an updated appraisal of the effect of adrenergic receptor modulation on variables related to human hemostasis by systematically reviewing the effect of adrenergic receptor-targeting drugs on scale variables related to hemostasis. By searching 3 databases for articles published between January 1st 2011 and February 16th, 2022 reporting effects on coagulation parameters from stimulation with α- or β-adrenergic receptor targeting drugs in humans regardless of baseline condition, excluding records different from original research and those not addressing the main aim of this systematic review. Risk of bias assessed using the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). Tables describing a pro-thrombotic anti-fibrinolytic state induced after β-adrenergic receptor agonist stimulation and the opposite after α1-, β-adrenergic receptor antagonist stimulation were synthesized from 4 eligible records by comparing hemostasis-related variables to their baseline. Notwithstanding this low number of records, experimental interventions included were sound and mostly unbiased, results were coherent, and outcomes were biologically plausible. In summary, this systematic review provides a critical systematic assessment and an updated elaboration, and its shortcomings highlight the need for further investigation in the field of hematology.

The Association of Improved Overall Survival with NSAIDs in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors

Article

Jan 2023
CLIN LUNG CANCER

Background: Immune checkpoint inhibitors (ICI) are commonly used in the management of patients with advanced non-small cell lung cancer (NSCLC), but response is suboptimal. Preclinical data suggest ICI efficacy may be enhanced with concomitant nonsteroidal anti-inflammatory (NSAID) medications. Patients and methods: In this retrospective study, the Veterans Health Administration Corporate Data Warehouse was queried for patients diagnosed with NSCLC and treated with ICI from 2010 to 2018. Concomitant NSAID use was defined as NSAID dispensation by a VA pharmacy within 90 days of the any ICI infusion. To mitigate immortal time bias, patients who started NSAIDs 60 or more days after ICI initiation were excluded from analysis. Survival was measured from start of ICI. Results: We identified 3634 patients with NSCLC receiving ICI; 2336 (64.3%) were exposed to concomitant NSAIDs. On multivariable analysis, NSAIDs were associated with better overall survival (HR = 0.90; 95% CI, 0.83-0.98; P = .010). When stratifying by NSAID type, diclofenac was the only NSAID with significant association with overall survival (HR = 0.75; 95% CI, 0.68-0.83; P < .001). Propensity score matching of the original cohort yielded 1251 patients per cohort balanced in characteristics. NSAIDs remained associated with improved overall survival (HR = 0.85; 95% CI, 0.78-0.92; P < .001). Conclusion: This study of Veterans with NSCLC treated with ICI demonstrated that concomitant NSAIDs are associated with longer OS. This may indicate that NSAIDs can enhance ICI-induced antitumor immunity and should prospectively validated.

Bodywide ecological interventions on cancer

Article

Jan 2023

Historically, cancer research and therapy have focused on malignant cells and their tumor microenvironment. However, the vascular, lymphatic and nervous systems establish long-range communication between the tumor and the host. This communication is mediated by metabolites generated by the host or the gut microbiota, as well by systemic neuroendocrine, pro-inflammatory and immune circuitries—all of which dictate the trajectory of malignant disease through molecularly defined biological mechanisms. Moreover, aging, co-morbidities and co-medications have a major impact on the development, progression and therapeutic response of patients with cancer. In this Perspective, we advocate for a whole-body ‘ecological’ exploration of malignant disease. We surmise that accumulating knowledge on the intricate relationship between the host and the tumor will shape rational strategies for systemic, bodywide interventions that will eventually improve tumor control, as well as quality of life, in patients with cancer. Moving away from the traditional ‘tumor-centric’ view, the authors explore how systemic biology, as well as aging, co-morbidities and co-medications, all interact and influence cancer development and progression.

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