Marine peptides in breast cancer: Therapeutic and mechanistic understanding

Abstract

Breast cancer is the most prevalent invasive form of cancer in females and posing a great challenge for overcoming the disease burden. The growth in global cancer deaths mandates the discovery of new efficacious natural anti-tumor treatments. In this regard, aquatic species offer a rich supply of possible drugs. Studies have shown that several marine peptides damage cancer cells by a broad range of pathways, including apoptosis, microtubule balance disturbances, and suppression of angiogenesis. Traditional chemotherapeutic agents are characterized by a plethora of side effects, including immune response suppression. The discovery of novel putative anti-cancer peptides with lesser toxicity is therefore necessary and timely, especially those able to thwart multidrug resistance (MDR). This review addresses marine anti-cancer peptides for the treatment of breast cancer.

Full text

Biomedicine & Pharmacotherapy 142 (2021) 112038
Available online 16 August 2021
0753-3322/© 2021 Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Marine peptides in breast cancer: Therapeutic and
mechanistic understanding
Salman Ahmed
a
, Hamed Mirzaei
b
, Michael Aschner
c
, Ajmal Khan
d
, Ahmed Al-Harrasi
d
,
*
,
Haroon Khan
e
,
*
a
Department of Pharmacognosy, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi, Karachi 75270, Pakistan
b
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
c
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
d
Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Postal Code, 616, Birkat Al Mauz, Nizwa, Oman
e
Department of Pharmacy, Abdul Wali Khan University Mardan, 23200, Pakistan
ARTICLE INFO
Keywords:
Marine peptides
Protein hydrolysate
Apoptosis
Metastasis
Cell cycle arrest
ABSTRACT
Breast cancer is the most prevalent invasive form of cancer in females and posing a great challenge for over-
coming disease burden. The growth in global cancer deaths mandates the discovery of new efcacious natural
anti-tumor treatments. In this regard, aquatic species offer a rich supply of possible drugs. Studies have shown
that several marine peptides damage cancer cells by a broad range of pathways, including apoptosis, microtubule
balance disturbances, and suppression of angiogenesis. Traditional chemotherapeutic agents are characterized by
a plethora of side effects, including immune response suppression. The discovery of novel putative anti-cancer
peptides with lesser toxicity is therefore necessary and timely, especially those able to thwart multi drug
resistance (MDR). This review addresses marine anti-cancer peptides for the treatment of breast cancer.
1. Introduction
Breast cancer is among the most prevalent cancers in women.
Around 0.62 million deaths in 2018 were caused by breast cancer, ac-
cording to Globocan 2018 gures from the International Organization
for Research on Cancer (I.A.R.C.). At the present rate, the number of
incidents is forecasted to increase to 3.05 million, and the death toll will
approximate 7 million by 2040 [1]. Cancer is conventionally treated
with chemotherapy, radiation, and surgery [2]. Conventional cancer
chemotherapy has many side effects, and it often targets multiple or-
gans. It is subject to MDR caused by over-expression of membrane
transporters, which may expel intracellular anti-cancer drugs, thus
decreasing drug accumulation and efcacy [3]. Furthermore, radiation
therapy and surgery increase the probability of cancer invasion [2].
Accordingly, developing new efcacious anti-cancer drugs is required
[4,5].
Extensive development initiatives have been underway to acquire
effective compounds of natural origin [6,7]. Approximately 71% of
Earth’s atmosphere is aquatic, rendering it an enormous reservoir of
novel bioactive substances of rare and special chemical characteristics.
Sea species are a treasure trove of anti-cancer drugs. Over the last
decade, numerous studies have shown that marine products could act as
anti-tumor agents and play a preventive role in tumor management,
underlying their promise in the discovery of novel and efcient phar-
maceuticals [4].
More than 50% of the FDA-approved medications in the 1980s and
Abbreviations: Akt, Serine / threonine protein-kinase family protein-kinase B; APAF-1, Apoptotic Peptidase-Activating Factor-1; BAD, BCl-2 / Bcl-X associated
death-domain protein; BAK, BCl-2 homologous antagonist - killer protein; BAX, BCl-2-associated x protein; Bcl-2, B-Cell lymphoma 2; Bcl-xL, B-Cell lymphoma-extra
large; Casp, Caspase; CXCR4, C-X-C chemokine-receptor type-4; Cyt c, cytochrome c; ErbB3, V-erb-b2 Erythroblastic Leukemia Viral Oncogene Homolog 3 (avian);
ERK1/2, Extracellular Signal Regulated kinase ½; FoxO3a, Forkhead Box Protein O3; HIF1
α
, Hypoxia inducible factor 1alpha; MMP, matrix metalloproteinase; Mcl-1,
Myeloid Cell Leukemia-1; MDR, Multidrug Resistance; MRP1, Multidrug Resistance-associated Protein 1; PARP, Poly ADP-Ribose Polymerase; P-gp, P-glycoprotein;
PI3K, Phosphatidylinositol-3-Kinase; ROS, Reactive Oxygen Species; STAT3, Signal transducer and activator of transcription 3; TNBC, Triple-negative Breast Cancer
Cell; VEGF, Vascular Endothelial Growth Factor.
* Corresponding authors.
E-mail addresses: salmanahmed@uok.edu.pk (S. Ahmed), h.mirzaei2002@gmail.com (H. Mirzaei), michael.aschner@einsteinmed.org (M. Aschner), aharrasi@
unizwa.edu.om (A. Al-Harrasi), haroonkhan@awkum.edu.pk, hkdr2006@gmail.com (H. Khan).
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy
journal homepage: www.elsevier.com/locate/biopha
https://doi.org/10.1016/j.biopha.2021.112038
Received 19 June 2021; Received in revised form 1 August 2021; Accepted 7 August 2021

Biomedicine & Pharmacotherapy 142 (2021) 112038
2
1990s have aquatic life origin. Indeed, sea-derived medicines are a
signicant source of anti-cancer drugs [8]. Several marine-derived drugs
have been approved as anti-cancer drugs, since the original approval of
cytarabine in 1969. The discovery of Didemnin B, obtained from Tridi-
demnum solidum in 1981 and dolastatin 10 from Dolabella auricularia in
1987, represents a critical point in the synthesis of marine-derived
cancer chemotherapy peptides [9]. Bioactive peptides from natural
aquatic products, including small marine peptides [10], have shown
efcacy as potential drug candidates with distinct modulations of
several molecular pathways [11].
There are numerous reasons as to why marine peptides have drawn
attention in the search for anti-cancer drugs. They have some signicant
benets over proteins or antibodies, such as small size, simple
manufacturing, readily modied, cell membrane-crossing capability,
low drug-drug interaction, chemical, and biological versatility. An
additional value is the fewer number of adverse side effects due to lack
of accumulation in the kidneys or liver [12–15]. The current review is
predominantly focused on the underlying mechanisms of marine pep-
tides in the treatment of breast cancer coupled with their therapeutic
potential.
2. Marine anti-cancer peptides
Marine peptides represent one of the most versatile sources of ther-
apeutically effective drug molecules [16]. Marine anti-cancer peptides
have been extracted from cyanobacteria, sponges, mollusks, ascidians,
algae, fungi, bacteria (actinomycete and streptomyces), and protein
hydrolysates from sh, amphibians, crocodiles, and turtles. Marine
peptides can be categorized as linear and cyclic peptides. Linear peptides
are formed by a straight amino acid chain connected with amide bonds
[17]. Hemiasterlin A-B (tripeptides) [18], Belamide A (tetrapeptides)
[19], Symplostatin, Dolastatin 10 and 15 (pentapeptides) [20] are
reported from sponges, cyanobacteria and mollusks.
Cyclic penta, hexa, hepta, decapeptides, depsipetides and oligopep-
tides from marine organisms are reported to possess anti-breast cancer
properties [17]. Galaxamide, A1- A5 (cyclic pentapeptides) [21], Mol-
lamide B (cyclic hexapeptides) [22]; Rolloamide A, Stylissatin B (cyclic
heptapeptides) [23,24], Stylopeptide 2 (cyclodecapeptides) [25], Lax-
aphycin B5, B6 and Wewakazole B (cyclic dodecapeptides) [26,27] are
obtained from algae, ascidia, sponge and cyanobacteria. Cordyhepta-
peptide C-E (cyclic heptapeptides) is obtained from marine derived
fungus [28]. Cyclic depsipeptides have a more complicated structure,
with ester bonds substitutes for amide bonds secondary to the presence
of hydroxy acid in the peptide framework [9,17].
Numerous anti-cancer cyclic depsipepides have been recorded from
marine organisms. Desmethoxymajusculamide C [29], Cocosamides A-B
[30], Hantupeptin A-C [31], Malyngamide 3 [30], Pitiprolamide [32],
Pitipeptolide A-F [33], Isomalyngamide A and A-1 [34], Largazole [35];
Cryptophycin [36] Cryptophycin 1 [37], Coibamide A [38,39] are ob-
tained from cyanobacteria. Jaspamide / Jasplakinolide A-P [40], Geo-
diamolide A-E, H, I [41–43], Pipecolidepsin A-B [44] from sponge;
Kahalalide F and Elisidepsin [45,46], Kulokekahilide-2 [47] from
mollusk; Dehydrodidemnin B (Aplidin / Plitidepsin) from ascidia Apli-
dium albicans [48] and Ohmyungsamycin A-B from streptomyces [49]
are cyclic depsipeptides with antibreast cancer properties.
Cyclic pentadepsipeptide Sansalvamide has been isolated from fun-
gus Fusarium sp [50]. Kailuin A-D (cyclic acyldepsipeptides) [51]. Thi-
ocoraline (cyclic thiodepsipeptide) [52] and Marthiapeptide A
(polythiazole cyclic peptide) [53] have been isolated from bacteria.
Macrocyclic peptide, Diazonamide A has been isolated from ascidia
Diazona angulata [54]. Cyclic oligopeptides are cyclic peptides consist-
ing of 2–20 amino acids formed by nonribosomal peptide synthesis [17].
Efrapeptin G from fungus Acremonium sp. is one such example [55].
Lipopeptides are linear, or cyclic lipid acylated peptides, typically
Fig. 1. Scheme of two of the involved pathways in apoptosis.
S. Ahmed et al.

Biomedicine & Pharmacotherapy 142 (2021) 112038
3
with the fatty acid side chain [9]. Several anti-cancer Lipopeptides have
been isolated from marine sources, including Curacin A-C, Somocysti-
namide A from cyanobacteria Lyngbya majuscula, and Schizothrix sp [56,
57]. Iturin A from bacteria Bacillus megaterium [58]. In triple negative
breast cancer, the Cyclo (L-Leucyl-L-Prolyl) a marine peptide has shown
propensity to target the EGFR and CD151 signaling pathway [59].
Marine Protein hydrolysates represent a family of nutraceuticals that
can prevent cancer [60]. Protein hydrolysates are characterized as oli-
gopeptides and free amino acid complex mixtures with antioxidant,
antiproliferative, antihypertensive, and antimicrobial effects [60,61].
Enzymatic hydrolysis is more likely to improve free radical scavenging
activity [62]. Protein hydrolysates obtained from sh [60], amphibians
[63] and turtles [64] have also been shown to possess anti-breast cancer
properties.
Marine anti-cancer peptides modulate/regulate a number of cellular
and molecular pathways, like DNA defense, cell-cycle control, apoptosis
initiation, angiogenesis suppression, migration, invasion, and metastasis
inhibition [4,5,8,65,66]. The current topic emphasizes the importance
of large marine peptides as an essential tool for discovering novel
anti-breast cancer treatments addressing their mechanistic effects.
3. Mechanistic insights
3.1. Apoptosis
A successful anti-cancer agent should have multidimensional
apoptotic targets [67,68]. Intrinsic and extrinsic pathways are linked to
caspase-3 (Casp-3) activation and induce DNA damage, nuclear and
cytoskeletal protein destruction, protein cross-linking, apoptosis body
development, and nally, phagocytic cell uptake (Fig. 1). The intrinsic
pathway is controlled by the Bcl-2 protein, releases Cyt c, and reacts
with APAF-1 to produce a platform for Casp-3, -7, and -9 activation.
Extrinsic pathways do not include mitochondria and are activated by
cell-surface death receptors [69–71].
Cyt c discharge from mitochondria plays a pivotal role in apoptosis
induction, causing a sequence of biochemical reactions culminating in
activation of Casps and subsequent cell death [72,73]. C-phycocyanin
induces apoptosis in BT-474, HBL 100, MCF7, MDA MB-231, and
SKBR-3 cells in vitro by Cyt c release and the ensuing activation of Casps
-9 [74,75]. Mere15, a linear polypeptide formed by Meretrix meretrix,
mediates Cyt c discharge and Casp-3,-9 and PARP cleavage [76]. Iturin
A, a lipopeptide formed by Bacillus megaterium mediates the release of
Cyt c, Casp-3,-9 and PARP in MCF7, T47D and MDA-MB-231, -468 [77].
Casps act as core apoptosis executors and are activated upon pro-
teolytic cleavage [78]. For example, symplostatin 1 treatment increases
the activity of Casp-3 in MDA-MB-435 and NCI/ADR leading to cell
death with IC
50s
of 0.15 and 2.9 nM, respectively [20],. Jaspamide A-P
induces apoptosis by increasing Casp-3 in MCF7 [40]. Activation of
Casp-3,-7,-8 and-9 has been detected in response to dolastatin 10 and 15
treatment [54]. Curacin A-C [56], Mere15 [76] Somocystinamide A
[57], Dehydrodidemnin B [48] Coibamide A [39], Cryptophycin [79]
has shown the same behavior in MCF7, MCF-15, MDA-MB-231 and -435.
Galaxamide and Galaxamide analogs A1-A5 have shown cytotoxicity
against MCF7 cell-lines by activating Casp-3, -9 and PARP [21]. Simi-
larly, Keyhole limpet hemocyanin (KLH) marine peptides enhances
apoptotic activity in MCF7 cells by 250 ng mL
-1
[48,80].
The combination of Bcl-2 inhibition and Bax induction is a successful
means for initiating apoptosis [22]. Jaspamide A-P induces apoptosis in
MCF7 by stimulating Casp 3, increasing Bax, decreasing Bcl-2 and PARP
protein proteolysis [40]. Symplostatin shows an analogous effect in
MDA-MB-435 and NCI/ADR with IC
50 s
of 0.15 and 2.9 nM, respectively
[20,81]. Similarly, C-phycocyanin induced apoptosis in BT-474,HBL
100, MCF7, MDA-MB-231 and SKBR-3 cells [74,75]. Dolastatin 10 and
15 [8,82]; Mere15 leads to the same response in MCF-15, triggered by
p53 [76]. BAX upregulation and Bcl-2, Mcl-1, Bcl-xL, downregulation in
MDA-MB-231 and MCF7 cells has been noted upon Iturin A [83] and
Dehydrodidemnin B treatments [48,84]. Tuna hydrolysate protein
(Thunnus tonggol) has shown cytotoxicity in MCF7 cells with IC
50 s
of
1.39 mg mL
-1
causing apoptosis by increased Casp-3, -9, PARP, Bcl-2,
Bax, and p53 expressions [85].
The PI3K/AKT pathways plays an important role in controlling cell
cycle and survival. AKT inhibition reduces the level of phosphorylated
Bad, Bax, Bak, triggers Cyt c release, and activates Casp-9 and regulates
p53-dependent apoptosis [40]. PI3K/AKT inhibition and decreased
ErbB3 have been shown to lead to cell cycle arrest and Bax and Bak
activation [86]. Kahalalide F causes PI3K/AKT inhibition and ErbB3
depletion in MCF7, SKBR3 and BT474 cells [45,87,88]. Elisidepsin
(PM02734, Irvalec®), a Kahalalide F synthetic derivative, has shown
cytotoxic activity in MDA-MB-231, -361, -435 SKBR3 cells through
PI3K/AKT inhibition and ErbB3 depletion [46,87,89]. Dolastatins has
shown an analogous response [90]. FoxO3a is a tumor suppressor, and
has been shown to downregulate Akt transcription factor and induce
apoptosis [83]. Iturin A has been shown to downregulate AKT phos-
phorylation and upregulate FoxO3a in MCF7, MDA-MB-231,-468 and
T47D cells [58].
3.2. Antimitotic
Antimitotic drugs act through stabilization, destabilization of
microtubule dynamics [91–93]. The microtubule system is essential for
mitosis and cell division, making it an effective anti-cancer drugs’ target.
Microtubules and microtubule-associated proteins are the major con-
stituents of the mitotic spindle having a crucial role in cell division.
Alterations in the tubulin-microtubule equilibrium leads to degradation
of the mitotic spindle, interrupting the cell cycle during the
meta-anaphase transformation, ultimately resulting in cell death [94].
Belamide A [19], Diazonamide A [54,95] and MML from mollusk Mer-
etrix meretrix [96] have been shown to exhibit cytotoxicity in MCF7 cells
by increasing cell membrane permeability and tubulin depolymeriza-
tion. Hemiasterlin, Hemiasterlin A, and B interrupt the G2-M phase
through disrupting microtubule dynamics in MCF 7 cells with IC50
0.5–7 nM [18]. Hemiasterlin and Hemiasterlin C arrest the G2-M phase
secondary to microtubule depolymerization in MDA-MB-435 cells with
IC
50 s
of 0.0154 and 0.4002
μ
g mL
−1
, respectively [97]. Similarly,
Microcionamide A, B [98] and Milnamide A - D [42,99] cause micro-
tubules depolymerization in MCF7, SKBR3, and MDA-MB-435 cells.
Scleritodermin A, a cyclic peptide, has been shown to be active in SKBR3
cells with IC
50 s
0.67 µM, and inhibited microtubule polymerization and
G2-M phase arrest [100]. Symplostatin 1 (dolastatin 10 analog) from
cyanobacteria Symploca sp. Has shown signicant anti-cancer effects in
murine mammary 16/C mouse xenograft model (early-stage mammary
adenocarcinoma). Increased Casp 3 increment, decreased Bcl-2 decre-
ment and microtubular depolymerization have been suggested as po-
tential anti-cancer mechanisms in mediating these effects [81].
Microtubule stabilizing agents accelerate microtubule polymeriza-
tion and damage the cytoskeleton and spindle cancer cells framework,
thus disrupting mitosis [91,94]. Cryptophycin has shown marked cyto-
toxicity in MCF7 (IC
50
of 0.016 nM), MCF-7/ADR (IC
50
value of
0.017 nM) and MDA-MB-435 (IC
50
of 50 pM) cells by stabilizing spindle
microtubules [36,37,101].
3.3. Antimetastatic
Microlaments have an essential role in cell migration. Actin poly-
merization inhibition results in microlament disruption, reducing cell
motility, and mitigates metastatic progression of neoplastic cells [102].
Desmethoxymajusculamide C is potent against MDA-MB-435 (IC
50
0.22 µM) cells, via actin microlament disruption [29]. Geodiamolides
A, B, D, E, H, and I have been shown to disrupt the actin laments in
T47D, MCF7, and MDA-MB-435 cells [42,43]. By positively affecting the
STAT3 pathway, MMP2 and MMP9 are subjected to upregulation and
facilitate cancer invasion. STAT3 inhibition leads to apoptosis and
S. Ahmed et al.

Biomedicine & Pharmacotherapy 142 (2021) 112038
4
suppresses metastasis in cancer cells [103]. C-phycocyanin inhibits
STAT3 in MCF7 and inhibits metastasis [75].
3.4. Antiangiogenic
Angiogenesis plays a central function in carcinogenesis (Fig. 2)
[104]. VEGF is abundantly expressed in cancer cells and is the key to
angiogenesis activation [105]. The angiogenesis mechanisms include
ERK1/2, CXCR4, HIF1
α
and Akt [106,107]. MMP2 and MMP9 also play
an essential role in tumor invasion and metastases [108]. Petrosaspongia
sponge Mycothiazole blocked HIF1
α
in T47D (IC
50
1 nM) along with
repression of the HIF1 reference gene VEGF expression [109].
C-phycocyanin [74], Isomalyngamide A and A-1 [34], and Coibamide A
[38,39] inhibit MCF7 and MDA-MB-231 cell migration by decreasing
VEGFR2 expression and MMP-9.
3.5. Cell cycle arrest
Disruption of the cell cycle is closely linked to apoptosis [110–114].
Activation of the cyclin-dependent kinase (Cyclin D1 and Cyclin E) in-
hibitors, p21 and p53 suppresses tumor growth and protects against
DNA damage by halting the cell cycle and regulates apoptosis
[115–117]. Coibamide A has shown G
1
phase arrest in MDA-MB-231
cells at GI
50
value of 2.8 nM [38,39]. Thiocoraline, a cyclic thiodep-
sipeptide from Micromonospora sp. displayed G1 phase arrest in SKBR3
cells with a GI
50
value of 2.2 nM [52]. C-phycocyanin [74,75] and
Dehydrodidemnin B (Aplidin / Plitidepsin) [118] induced G1-G2 phase
arrest by decreasing cyclin D1, cyclin E; and CDK2 and increasing p21 in
MCF7 and MDA-MB-231 cells, respectively. Hemiasterlin and Hemi-
asterlin A- C [18,97] and HTI-286 [119] induced G2-M phase arrest in
MCF7, MDA-MB-435 and MX-1W cells. Similarly, Mere15 induced p53
upregulation and cell cycle arrest in MCF-15 cells [76]. Peptides from
Porphyra haitanesis have shown cells cytotoxicity and G0/G1 phase ar-
rest in MCF7 with IC
50
of 200.97
μ
g mL
-1
[120].
3.6. Oxidative stress
Oxidative stress triggered by mitochondrial disorders is induced by
ROS (Reactive Oxygen Species) generation. A variety of factors such as a
hypoxia, antioxidants, ER stresses, and NADPH contribute or inhibit
ROS generation (Fig. 3) [121]. Aplidin induces apoptosis in
MDA-MB-231 cells by promoting increased GSSG/GSH ratio [122]. DNA
fragmentation, the most common DNA damage, is directly associated
with oxidative stress [123]. Cryptophycin 1 in MDA-MB-435 cells has
been shown to induce DNA fragmentation [37]. Iturin A has also been
shown to induce DNA fragmentation in MCF7, T47D, MDA-MB-231 and
-468 cells [58]. C-phycocyanin scavenges ROS and increases γ-H2AX in
MCF7 cells, an indicator of DNA damage [74,124]. Binucleated cells are
seen as a consequence of oxidative stress in response to symplostatin
[20].
Fig. 2. A schema of angiogenesis and its involved factors.
Fig. 3. Various factors that affect ROS generation.
S. Ahmed et al.

Biomedicine & Pharmacotherapy 142 (2021) 112038
5
3.7. Destruction of cancer cell membrane
Anti-cancer peptides (ACPs) cause cell membrane depolarization,
leading to tumor cells’ failure to sustain normal osmotic pressure and a
massive leakage of cytoplasmic material [125,126]. Anti-proliferative
peptides destroy cancer cells by necrotic mechanisms that trigger cell
membrane lysis [60,127,128]. Anti-cancer peptides cause membrane
destabilization, cell lyses, and the ensuing death of cancer cells [129,
130]. Anti-proliferative peptides with high ROS reduced activity can
prevent cancer incidence [60]. Protein hydrolysate from Thunnus tonggol
muscle by-product showed an anti-proliferative activity in MCF7 cells
with IC
50 s
of 8.1 and 8.8
μ
M, respectively [131]. Gadus morhua Atlantic
cod, Pleuronectes platessa plaice and Micromesistius poutassou sh hy-
drolysates induced anti-proliferative activity of MCF7/6 and
MDA-MB-231 cells at 1 g L
−1
[132]. Loach (Misgurnus anguillicaudatus)
muscle hydrolysate obtained from the papain enzyme exhibits
anti-proliferative activity at 40 mg mL-1 MCF7 cancer cell line [133]. A
hydrolysate from Dosidicus gigas has shown toxicity in MCF7 cells, with
IC
50
value of 0.13 mg mL
-1
[134]. Antitumor peptides (RGVKGPR,
KLGPKGPR, and SSPGPPVH) from Cuora trifasciata turtle have been
shown to inhibit MCF7 cancer cells [64].
3.8. Unknown mechanism for anti-cancer activity of marine peptides
Ascidians mollamide B [22] and Spongian Callyptide A [122],
Criamide B [11,135], Pipecolidepsin A-B [44], Rolloamide A [23],
Stylissatin B [24] and Pembamide [136] induced potent cytotoxicity
with unidentied mechanism. Kulokekahilide-2 from mollusks [47] and
malyngamide 3 [30] cocosamides A and B [30], wewakazole B [27]
from cyanobacteria are other examples. Anti-cancer marine peptides
also include Kailuins A–D from bacteria [51,137], Marthiapeptide A
from actinomycetes [53], Ohmyungsamycin A and Ohmyungsamycin B
from streptomyces [49], Cordyheptapeptide C -E [28], Sansalvamide
[50] and Efrapeptin G [138] from the marine sponge-derived fungus.
The peptide from saltwater clam Ruditapes philippinarum has shown
cytotoxicity in MDA-MB-231 cells with IC
50
of 1.58 mg mL
-1
[139,140].
4. Marine peptides in MDR cancers
The leading causes of chemotherapy failure are inherent or acquired
drug resistance due to overexpression of P-gp [141–143]. MDA-MB-231,
-436,-468, BT20, BT-549, SKBR3, and Hs578T are useful for studying
molecular aberrations and mechanisms inuenced by these aberrations
in TNBC [144].
Hemiasterlin and Hemiasterlin C [97], HTI-286 [119,145] and Mil-
namide A - D [42,99] depolymerize MDA-MB-435 breast cancer mi-
crotubules showed their less interaction with MDR P-glycoprotein
(P-gp). Preclinical experiments have demonstrated that HTI-286 induces
the degradation of the tumor and reduces human MX-1W (MRP1 over-
expressed) breast carcinoma xenografts in mice paclitaxel and vincris-
tine were unsuccessful due to P-gp associated resistance [119].
Symplostatin 1 (dolastatin 10 analog) showed Bcl-2 inhibition and
microtubule depolymerization in MDR breast cancer MDA-MB-435 (IC
50
0.15 nM) and NCI/ADR (IC
50
2.9 nM) cells [20]. However, Symplostatin
1 showed marginal antitumor activity against MDR tumors mammary
adenocarcinoma 17/Adr and mammary adenocarcinoma 16/C/Adr
(adriamycin-resistant murine early stage solid tumors) [81]. Crypto-
phycin, a cytotoxic macrocyclic depsipeptide isolated from cyanobac-
teria Nostoc sp., is an antimicrotubule agent that tends to be a weaker
P-gp substrate than Vinca alkaloids.
Breast carcinoma cells are abundantly drug resistant due to increased
expression of P-gp and are signicantly less cryptophycin resistant than
colchicine, vinblastine and taxol. Cryptophycin has shown antimitotic
activity in breast cancer MCF7 and MCF7/ADR cells with IC
50 s
of 0.016
and 0.017 nM respectively through microtubule stabilization [36].
Cryptophycin (50 pM) also induces mitotic arrest in MDA-MB-435 by
developing distorted mitotic spindles without affecting the interphase
microtubules [37]. Geodiamolide D-E demonstrated antiproliferative
action toward MDA-MB-435, a P-gp upregulating MDR cell line, with
actin lament interruption [42]. Kulokekahilide-2 is also active towards
MDA-MB-435 cells, with an IC
50
of 14.6 nM [47]. Stylopeptide 2 had
antiproliferative effects on BT-549 and HS 578 T cells at a dosage of
10
−5
M [25]. Ohmyungsamycin A and Ohmyungsamycin B has been
shown to exhibit antiproliferative effects against MDA-MB-231 with
IC50s of 0.688 and 12.7
μ
M, respectively [49]. Interestingly, there was
no cytotoxicity (IC50 >40
μ
M) in normal epithelial MRC-5 cells [49].
Largazole inhibits MDA-MB-231 with GI
50
value of 7.7 nM over normal
mammary NMuMG cells with IC
50
of 122 nM [35]. C-phycocyanin af-
fects cancer cell cycle propagation by G0/G1 step arrest in
MDA-MB-231, indicating weak P-gp transport substrate [146]. Pipeco-
lidepsin A, Pipecolidepsin B, Pembamide, and Callyptide A inhibit
MDA-MB-231 cellular growth with IC
50 s
of 0.7, 0.02, 3.35, and 29 µM,
respectively [44,122,136]. DZ-2384 has antitumor activity by inhibition
of mitotic spindle formation in metastatic TNBC (MDA-MB-231-LM2),
lacks neurotoxicity in rats, and signicantly increases survival [147].
Frog-derived peptide Hymenochirin-1B [63] and Alyteserin-2a [148]
have been shown to be cytotoxic to MDA-MB-231 cells. Micro-
cionamides A and B are cytotoxic to SKBR3 cells [98]. Kahalalide F
induced cytotoxicity in SKBR3 via PI3K-AKT inhibition [45,87]. Eli-
sidepsin has shown similar response in MDA-MB-231, -361, -435 and
SKBR3 [46,87].
5. Marine peptides in clinical trial status
Up to now, Hemiasterlin (E7974) [149] and Eribulin mesylate
(Halaven®) [87] have been approved by FDA for breast cancer. Pliti-
depsin (Aplidin®) [87], and Keyhole Limpet Hemocyanin (Immuco-
thel®) [149] have been approved by FDA and ATGA for different
cancers, but clinical trials for breast cancer are needed.
Dolastatin 10 have not advance to clinical trials due to its insigni-
cant therapeutic index and substantial toxic side effects. Thus, further
clinical trials are discontinued, and structural modications have been
established to enhance therapeutic efcacy, especially against TNBC
[13,150]. LU 103793 was evaluated in patients for efcacy and tolera-
bility in metastatic breast cancer but experienced neutropenia, asthenia,
stomatitis, myalgia, and hypertension resulting in cessation of further
assessment [151]. Soblidotin (TZT-1027) was engineered to retain
potent antitumor efcacy while reducing the parent drug’s toxicity,
dolastatin 10. In human MX-1 mammary carcinoma xenografts models,
soblidotin showed very efcient outcomes [152]. Soblidotin has reached
phase I clinical trials and has demonstrated less neurotoxicity than other
tubulin inhibitors with a suggested dosage of 1.8 mg m
2
[12,153].
High toxicity, low solubility, and limited life span resulted in the
Didemnin B clinical trials’ withdrawal in support of the second gener-
ation didemnin, plitidepsin [9,15]. Dehydrodidemnin B, commonly
known as (Aplidin or Plitidepsin), is more active than Didemnin pre-
clinical models against breast cancer cell lines and so far has not shown
evidence of life-threatening neuromuscular toxicity [15]. Plitidepsin is
in phase III clinical research for breast, melanoma, and non-small cell
lung cancers [154]. Elisidepsin (PM02734, Irvalec®), one of the most
potent analogs of Kahalalide F, was chosen for phase II clinical research
owing to its benecial therapeutic index and non-toxic prole [8].
Taltobulin or SPA-110 (HTI-286) is a synthetic hemiasterlin analog
with promising antimitotic action. This compound has progressed to
clinical trials for to its potential role in suppressing colchicine-like
tubulin polymerization and prevent cell division in MCF7 and MX-1W.
The terminations of HTI286 phase I clinical trials due to its toxicity
mandate the development of new synthetic formulations with lesser
adverse reactions [119,155].
S. Ahmed et al.

Biomedicine & Pharmacotherapy 142 (2021) 112038
6
Table 1
Anticancer effects of Marine peptides in the different reported studies.
Peptides Marine sources
(Species name)
Active derivative In vitro In vivo Anticancer
Mechanisms
References
Human
breast
cancer
cell lines
IC50s Experimental
model
Dose
Desmethoxymajusculamide
C
Cyanobacteria
(Lyngbya majuscula)
Cyclic depsipeptide MDA-
MB-435
0.22 µM – – Actin microlament
disruption
[29]
Isomalyngamide A and A-1 MDA-
MB-231
A, 0.06; A-1: 0.337
μ
M – – VEGFR2 ↓ and MMP-9
↓
[34]
Cocosamides A-B MCF7 A: 30; B: 39
μ
M – – ↓ cell viability [30]
Hantupeptin A-C A: 4; B:0.5; C: 1.0 µM – – [31,163]
Malyngamide 3 29
μ
M – – [30]
Pitiprolamide 33
μ
M – – [32]
Pitipeptolide A-F A:13; B: 11; C: 73; D and
E: >100; F: 83
μ
M
– – [33]
Wewakazole B Cyclic
dodecapeptide
MCF7 0.58
μ
M – – [27]
Curacin A-C Lipopeptide A: 0.72; B: 0.82; C:
2.3
μ
M
– – Caspase 3↑;
Microtubule
depolymerization
[56]
Somocystinamide A Cyanobacteria
(Lyngbya majuscula
and Schizothrix sp.)
210 nM – – Caspase 8 ↑ [57]
Largazole Cyanobacteria
(Symploca sp.)
Cyclic depsipeptide MDA-
MB-231
7.7 nM – – ↓ cancer cell growth [35]
Belamide A Linear tetrapeptide MCF7 1.6
μ
M – – Microtubule
destabilization
[19]
Symplostatin Linear
Pentapeptide
MDA-
MB-435;
NCI/ADR
0.15 nM / 2.9 nM – – Caspase 3↑; Bcl2↓;
Bax↑; PARP ↑;
Microtubules
depolymerization
[20]
– – murine
mammary 16/C
mouse xenograft
model
1.25 mg/
kg i.v.
[81]
Cryptophycin Cyanobacteria
(Nostoc sp.)
Cyclic depsipeptide MCF7 0.016 nM – – Microtubule
stabilization
[36]
MCF-7/
ADR
0.017 nM – –
Cryptophycin 1 MDA-
MB-435
50 pM – – DNA fragmentation;
Microtubule
stabilization; Caspase
3 ↑
[37]
Laxaphycin B5, B6 Cyanobacteria
(Phormidium sp.)
Cyclic
dodecapeptide
MDA-
MB-231
GI
50
(µM) =B5: 2.2; B6:
0.81
– – ↓ cell viability [26]
MDA-
MB-435
GI
50
(µM) B5: 1.2; B6:
0.58
– –
Coibamide A Cyanobacteria
(Leptolyngbya sp.)
Cyclic depsipeptide MDA-
MB-231
2.8 nM – – Caspase 3↑, -7 ↑;
VEGF↓; G
1
phase
arrest
[38,164]
C-phycocyanin Cyanobacteria
(Limnothrix sp. NS01
and Spirulina
platensis)
Peptide MCF7 15.43 µM – – DNA fragmentation;
Caspase-9 ↑; cyt c ↑;
Bcl2↓; Bax↑; PARP ↑;
Stat3 ↓
[74,75]
G1 - G2 phase arrest
(cyclin D1↓, cyclin E↓;
p21↑)
Antiangiogenic
(VEGFR2 ↓ and MMP-
9 ↓)
AKT inhibition;
γ-H2AX ↑; Production
of ROS and singlet
oxygen radicals
HBL 100 8.31 µM – –
BT-474 8.45 µM – –
SKBR3 15.73 µM – –
MDA-
MB- 231
5.98 µM – –
Galaxamide, A1- A5 Algae (Galaxaura
lamentosa)
Cyclic
pentapeptide
MCF7 Galaxamide: 14.09; A1:
9.4; A2: 9.64; A3: 7.23;
A4: 6.56; A5:
4.18
μ
g mL
−1
– – Caspase-9, -3 ↑; PARP
↑
[21]
Callyptide A Sponge
(Callyspongia sp.)
Cyclic peptide MDA-
MB-231
GI
50
=29 µM ↓ cell viability [122]
Criamide B Sponge (Cymbastela
sp.)
Peptide MCF7 6.8
μ
g mL
−1
– – [11,135]
Jaspamide A-P Sponge (Jaspis
splendans)
Cyclic depsipeptide A: 0.019; B: 3.41; C: 2; D:
0.05; E: 0.02; F: 30; G:
0.6; H: 30; J: 5; K: 0.48; L:
– – Caspase-3 ↑; Bcl2↓;
Bax↑; PARP ↑
[40]
(continued on next page)
S. Ahmed et al.

Biomedicine & Pharmacotherapy 142 (2021) 112038
7
Table 1 (continued )
Peptides Marine sources
(Species name)
Active derivative In vitro In vivo Anticancer
Mechanisms
References
Human
breast
cancer
cell lines
IC50s Experimental
model
Dose
0.61; M: 0.1; N: 33; O:
0.38; P: 12
μ
M
Geodiamolide A-B, H, I Sponge (Auletta sp.
and Geodia
corticostylifera)
A: 17.83; B: 9.82; H:
89.96; I: 65.70 nM
– – Actin lament
disruption
[43]
T47D A: 18.82; B: 113.90; H:
38.36; I: 115.30 nM
– – [43]
Geodiamolide H MDA-
MB-231
4.33 ×10
-7
M – – ↓ cancer cell growth [41]
Geodiamolide H HS 578 T 2.45 ×10
-7
M – –
Geodiamolide D-E MDA-
MB-435
D: 0.08; E: 0.25
μ
g mL
−1
– – Actin lament
disruption
[42]
Pipecolidepsin A-B Sponge
(Homophymia
lamellosa)
MDA-
MB-231
GI
50
=A: 0.7; B: 0.02
μ
M – – ↓ cell viability [44]
Rolloamide A Sponge (Eurypon
laughlini)
Cyclic
heptapeptides
MCF7 0.88 µM – – [23]
BT549 1.3 µM – –
MDA-
MB-231
2.2 µM – –
MDA-
MB-361
5.8 µM – –
MDA-
MB-435
0.40 µM – –
MDA-
MB-468
0.38 µM – –
Stylissatin B Sponge (Stylissa
massa)
MCF7 4.8
μ
M – – [24]
Stylopeptide 2 Sponge (Stylotella
sp.)
Cyclic decapeptide BT-549;
HS 578T
10
−5
M – – Antiproliferative
effect
[25]
Scleritodermin A Sponge
(Scleritoderma
nodosum)
Cyclic peptide SKBR3 0.67 µM – – Microtubules
depolymerization;
G2/M phase arrest
[100]
Hemiasterlin and
Hemiasterlin A-B
Sponge
(Hemiasterella minor,
Auletta sp.,
Cymbastela sp., and
Siphonochalina sp.)
Linear tripeptide MCF7 Hemiasterlin: 0.5; A: 2; B:
7 nM
– – [18]
Hemiasterlin and
Hemiasterlin C
MDA-
MB-435
Hemiasterlin: 0.0154;
Hemiasterlin C:
0.4002
μ
g mL
−1
– – [97]
HTI-286 MCF7 7.3 nM – – [119]
MX-1W 1.8 nM – –
– – MCF7 mouse
xenograft model
1 mg/kg
i.v. for 9
days
Antiproliferative
effect
[119]
– – MX-1W mouse
xenograft model
1.6 mg/
kg i.v.
Pembamide Sponge
(Cribrochalina sp.)
N-methylated
linear peptide
MDA-
MB-231
GI
50
=3.35
μ
M – – ↓ cell viability [136]
Microcionamide A-B Sponge (Clathria
(Thalysias) abietina)
MCF7 A: 125; B: 177 nM – – Microtubules
depolymerization
[98]
SKBR3 A: 98; B: 172 nM – –
Milnamide A and D Sponge (Auletta sp.
and Cymbastela sp.)
MDA-
MB-435
A: 6.02; D: 16.9 µM – – [99]
Milnamide B-C B: 1.48 ×10
−4
; C:
0.32 ±0.02
μ
g mL
−1
– – [42]
Mycothiazole Sponge
(Petrosaspongia
mycojiensis)
Mixed polyketide/
peptide-derived
compound
T47D 1 nM – – HIF1
α
inhibition;
VEGF ↓
[109]
Dolastatin 10 Mollusk (Dolabella
auricularia)
Linear
Pentapeptide
MCF7 0.06 nM – – Caspase 3 ↑; Bcl2↓;
Bax↑; PARP ↑; p53↑;
Microtubule
depolymerization
[54]
Dolastatin 15 0.9 nM – –
Kahalalide F Mollusk (Elysia
rufescens)
Cyclic depsipeptide 0.28 µM – – PI3K-AKT inhibition;
ErbB3 depletion
[45]
SKBR3 0.23 µM – –
BT474 0.26 µM – –
Elisidepsin MCF7 8 µM – – [46]
MDA-
MB-231
4.7 µM – –
MDA-
MB-361
1.25 µM – –
MDA-
MB-435
4.4 µM – –
SKBR3 6 µM – –
ZR-75–1 0.4 µM – –
Kulokekahilide-2 Mollusk (Philinopsis
speciosa)
MDA-
MB-435
14.6 nM – – ↓ cell viability [47]
(continued on next page)
S. Ahmed et al.

Biomedicine & Pharmacotherapy 142 (2021) 112038
8
Table 1 (continued )
Peptides Marine sources
(Species name)
Active derivative In vitro In vivo Anticancer
Mechanisms
References
Human
breast
cancer
cell lines
IC50s Experimental
model
Dose
Mere15 Mollusk (Meretrix
meretrix)
Polypeptide MCF-15 57.43
μ
g mL
−1
– – G2-M phase arrest;
Caspase 3, 9 ↑; cyt c ↑;
Bcl2↓; Bax↑; PARP ↑;
p53 ↑
[76]
Diazonamide A Ascidia (Diazona
angulata)
Macrocyclic
peptide
MCF7 1.9 nM – – Microtubule
depolymerization
[54]
DZ-2384 (synthetic
diazonamide)
BT-549 0.66 nmol – – [147]
GCRC
1735
7 nmol – –
GCRC
1915
17 nmol – –
MDA-
MB-231
7.7 nmol – –
MDA-
MB-436
2.8 nmol – –
– – MDA-MB-231-
LM2 mouse
xenograft model
4.5 mg/
m
2
i.v. for
28 days
Dehydrodidemnin B Ascidia (Aplidium
albicans)
Cyclic depsipeptide MCF7 50 nM – – G1 - G2 phase arrest
(cyclin D1↓; cyclin E↓;
p21↑), Caspase-9, −3
↑; Bcl2↓; Bax↑; PARP ↑
[48]
MDA-
MB-231
5 nM – – [84]
Mollamide B Ascidia (Didemnum
molle)
Cyclic
hexapeptides
MCF7 100 µM – – ↓ cell viability [22]
Cordyheptapeptide C-E Fungus
(Acremonium
persicinum SCSIO
115)
Cyclic
heptapeptide
MCF7 C: 3; D: 82.7; E: 2.7
μ
M – – [28]
Efrapeptin G Fungus
(Acremonium sp.)
Oligopeptide 0.027
μ
M MCF7 mouse
xenograft model
0.15 mg/
kg i.p. for
28 days
↓ cancer cell growth [55]
MDA-
MB-231
3.430
μ
M MDA-MB-231
mouse xenograft
model
0.3 mg/
kg i.p. for
28 days
T47D 0.057
μ
M – –
MDA-
MB-453
0.132
μ
M – –
Sansalvamide Fungus (Fusarium
sp.)
Cyclic
pentadepsipeptide
MAXF
401
0.02
μ
g mL
−1
– – ↓ cell viability [50]
Iturin A Bacteria (Bacillus
megaterium)
Lipopeptide MCF7 12.16 ±0.24 µM – – DNA fragmentation;
AKT inhibition;
FoxO3a↑; Bcl2↓; Bax↑;
PARP ↑; Bcl-xL ↓; cyt c
↑
[58]
T47D 26.29 ±0.78 µM – –
MDA-
MB-231
7.98 ±0.19 µM – –
MDA-
MB-468
13.30 ±0.97 µM – –
– – MDA-MB-231
mouse xenograft
model
10 mg/kg
i.v.
↓ cell viability [58]
Kailuin A-D Bacteria (BH-107) Cyclic
acyldepsipeptide
MCF7 GI
50
(
μ
g mL
−1
) =A: 3; B:
2; C: 4; D: 3
– – [51]
Kailuin D 39
μ
M – – [137]
Marthiapeptide A Bacteria
Marinactinospora
thermotolerans
SCSIO 00652)
Polythiazole cyclic
peptide
0.43
μ
M – – [53]
Proximicin A-C Bacteria
(Verrucosispora sp.)
Polyamide A: 24.6
μ
M; B: 12.1
μ
M;
C: 1.8
μ
M
– – [165]
Thiocoraline Bacteria
(Micromonospora sp.
L-13-ACM2–092)
Cyclic
thiodepsipeptide
SKBR3 GI
50
=2.2 nM – – G
1
phase arrest [52]
Ohmyungsamycin A-B Bacteria
(Streptomyces strain
SNJ042)
Cyclic
depsipeptides
MDA-
MB-231
A: 0.68 and B: 12.7
μ
M – – ↓ cell viability [49]
S. Ahmed et al.

Biomedicine & Pharmacotherapy 142 (2021) 112038
9
6. Conclusions and future perspectives
The most prevalent and fatal illness in women is breast cancer. The
available treatments are effective for cancer treatment but have side
effects. There is still an urgent need for novel medications to be effective
for the cancer therapy. The discovery of novel clinical chemotherapeutic
peptides from diverse aquatic life can be incorporated into breast cancer
prevention and care [156]. The lack of ethnomedicinal background,
technical difculties in collecting marine animals, particularly deep-sea
organisms; isolation and purication problems are obstacles in
anti-cancer peptides research [157]. Thanks to modern technology, it is
increasingly possible to extract samples from the sea and different
peptides from aquatic materials [158]. Marine peptides have demon-
strated possible anti-cancer activities against various forms of cancer,
such as cell growth inhibition, antimitotic activity (anti-tubulin effects),
apoptosis induction, and migration, invasion or metastasis inhibition.
These marine peptides have proven to be a valuable and exciting
resource for developing anti-cancer drugs and a platform for discovering
new cellular targets for therapeutic action [159]. Therefore, it is highly
relevant to deepen the study of marine peptides’ anti-cancer mecha-
nisms to develop new candidate compounds [160]. The tolerance of
cancer cells to chemotherapy is indeed one of the sources of modern
pharmacotherapy’s inefciency. Marine peptides act efciently as
MDR-threatening proteins. The more signicant part of the exploration
led to marine peptides; anti-cancer power is in vitro, making it difcult to
give the right determination on its helpfulness.
Of these compounds, only a few progressed to clinical studies, and a
relatively small number of peptides have successfully entered the
pharmaceutical pipeline and have been used clinically.
Numerous marine peptides are undergoing clinical trials, although
there is a widely unexplored area of marine protein hydrolysates [157].
Short half-life, low bioavailability, processing and manufacturing
problems, and protease susceptibility are signicant drawbacks of
therapeutic peptides [12–14,83]. For low cell membrane permeability,
cell penetrating peptides are used. Metabolic instability and short
half-life in circulation may be overcome by using D-amino acid substi-
tution, peptide cyclization, encapsulation with nanoparticles, pegyla-
tion, and XTEN conjugation. D-amino acid substitution reduces
immunogenicity [126,161,162]. Protein hydrolysates are an alternative
source of anti-cancer, antioxidant, and antiproliferative bioactive com-
pounds. However, further investigation is required on the cell cycle
mode or apoptosis of cancer cell lines. in vivo and in silico studies are also
necessary to identify and characterize the mechanism of action and
safety of marine peptides and protein hydrolysates to achieve complete
anti-cancer drug efcacy [8]. In particular, further analysis of the
variability of marine peptides in structural modication and modes of
action would provide a rich resource for creating unique and potent new
pharmaceuticals (Table 1).
Ethics approval and consent to participate
Not applicable.
Funding
The project was supported by grant from The Oman Research
Council (TRC) through the funded project (BFP/RGP/HSS/19/198).
CRediT authorship contribution statement
Salman Ahmed and Ajmal Khan written the initial draft. Hamed
Mirzaei drawn the gures. Michael Aschner proof read the article for
English and grammatic corrections. Ahmed Al-Harrasi and Haroon Khan
designed and supervised the overall review.
Competing interests
The authors of this article have no nancial conict.
Consent for publication
Not applicable.
Availability of data and materials
All datasets on which the conclusions of the manuscript rely are
presented in the paper
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