Preventive and therapeutic use of herbal compounds against doxorubicin induced hepatotoxicity: a comprehensive review

Abstract

Doxorubicin (DOX) is associated with numerous acute and chronic dose-related toxicities including hepatotoxicity. This adverse reaction may limit the use of other chemotherapeutic agents with hepatic excretion, and so, its prevention is an important issue. The aim of this study was to conduct a comprehensive review of in vitro, in vivo and human studies regarding the protective effects of synthetic and naturally-occurring compounds against DOX-induced liver injury. The search was conducted in Embase, PubMed, and Scopus databases using the following keywords: “doxorubicin,” “Adriamycin,” “hepatotoxicity,” “liver injury,” “liver damage,” and “hepatoprotective,” and all articles published in English were included without time restriction. Forty eligible studies to the end of May 2022 finally were reviewed. Our results demonstrated that all of these drugs, except acetylsalicylic acid, had considerable hepatoprotective effects against DOX. In addition, none of the studied compounds attenuated the antitumor efficacy of DOX treatment. Silymairn was the only compound which is assessed in human studies and showed promising preventive and therapeutic effects. Altogether, our results demonstrated that most of compounds with antioxidant, anti-apoptosis, and anti-inflammatory properties are efficacious against DOX-induced hepatotoxicity and may be considered as a potential adjuvant agent for prevention of hepatotoxicity in cancer patients, after fully been assessed in well-designed large clinical trials.

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Naunyn-Schmiedeberg's Archives of Pharmacology
https://doi.org/10.1007/s00210-023-02429-1
REVIEW
Preventive andtherapeutic use ofherbal compounds
againstdoxorubicin induced hepatotoxicity: acomprehensive review
FaezehMahmoudi1· OmidArasteh1· SepidehElyasi1
Received: 19 August 2022 / Accepted: 16 February 2023
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023
Abstract
Doxorubicin (DOX) is associated with numerous acute and chronic dose-related toxicities including hepatotoxicity. This
adverse reaction may limit the use of other chemotherapeutic agents with hepatic excretion, and so, its prevention is an
important issue. The aim of this study was to conduct a comprehensive review of invitro, invivo and human studies regard-
ing the protective effects of synthetic and naturally-occurring compounds against DOX-induced liver injury. The search
was conducted in Embase, PubMed, and Scopus databases using the following keywords: “doxorubicin,” “Adriamycin,”
“hepatotoxicity,” “liver injury,” “liver damage,” and “hepatoprotective,” and all articles published in English were included
without time restriction. Forty eligible studies to the end of May 2022 finally were reviewed. Our results demonstrated that
all of these drugs, except acetylsalicylic acid, had considerable hepatoprotective effects against DOX. In addition, none of
the studied compounds attenuated the antitumor efficacy of DOX treatment. Silymairn was the only compound which is
assessed in human studies and showed promising preventive and therapeutic effects. Altogether, our results demonstrated that
most of compounds with antioxidant, anti-apoptosis, and anti-inflammatory properties are efficacious against DOX-induced
hepatotoxicity and may be considered as a potential adjuvant agent for prevention of hepatotoxicity in cancer patients, after
fully been assessed in well-designed large clinical trials.
Keywords Doxorubicin· Adriamycin· Hepatotoxicity· Herbal compounds· Liver injury· Hepatoprotective
Abbreviations
DOX Doxorubicin
ROS Reactive oxygen species
NADPH Nicotinamide adenine dinucleo-
tide phosphate
AST Aspartate aminotransaminase
ALT Alanine aminotransaminase
SD rats Sprague-Dawley rats
PI3K Phosphoinositide3-kinase
TNBC cells Triple negative breast cancer cells
G10 10-Gingerol
Cdk-6 Cyclin-dependent kinase 6
GGT γ Glutamyl transferase
NM Nutrient mixture
RCD Regular chow diet
VCO Virgin coconut oil
ATP Adenosine triphosphate
LDH Lactate dehydrogenase
CkMB Creatine kinase myocardial band
DLA Daltone’s lymphoma ascites
GAE Ganoderma applantum Extract
LDL Low density lipoprotein
HDL High density lipoprotein
ALP Alkaline phosphatase
TG Triglycerides
PRV Pravastatin
LNE Lipid nanoemulsion
EAC-challenged mice Mice which injected with tumor
cells
TBARS Thiobarbituric acid reactive
substances
GSH Glutathione
CAT Catalase
SOD Superoxide dismutase
LD50 Median lethal dose
PARP Poly-ADP-ribose polymerase
ECG Electrocardiogram
* Sepideh Elyasi
elyasis@mums.ac.ir
1 Department ofClinical Pharmacy, School ofPharmacy,
Mashhad University ofMedical Sciences, P.O.
Box91775-1365, Mashhad, Iran

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CGA Chlorgenic acid
FAC Fluorouracil/doxorubicin/
cyclophosphamide
TE Transient elastography
RCT Randomized clinical trial
AC-T Doxorubicin/
cyclophosphamide-paclitaxel
AKBA Acetyl 11-keto-b-boswellic acid
Nrf2 NF-E2-related factor 2
BOS Boswellic acid
HO-1 Oxygenase-1
Sirt1 Silent information regulator 1
FOXO1 Forkhead box protein O1
Keap1 Kelch-like ECH-associated
protein-1
PCNA Proliferating cell nuclear antigen
GPx Glutathione peroxidase
GR Glutathione reductase
GST Glutathione-S-transferase
EC50 Half maximal effective
concentration
Cr Creatine
FN-1 Fibronectin
NIN Naringin
LA DL-alpha lipoic acid
GSSE Grape seed and skin extract
MDA Malondialdehyde
G6PD Glucose-6-phosphate
dehydrogenase
ATS Artemisinin
ATX Astaxanthin
AA Asiatic acid
ALP Alkaline phosphatase
LPO Lipid peroxidation
ZM Zataria multiflora
AHE Acacia hydaspica
POD Peroxidase
QR Quinone reductase
pCA P-Coumaric acid
ALB Albumin
ZJ Ziziphus jujuba
HSP70 Heat shock protein 70
IGF Insulin-like growth factor
IGFBP-3 Insulin-like growth factor binding
protein
ETC Electron transport chain
Introduction
Cancer is one of the most common human diseases with the
incidence rate of over 440 per 100,000 men and women,
and a total number of 19.3 million people are diagnosed
annually. This devastating disease is the second leading
cause of human mortality after cardiovascular disease,
accounting for up to 10 million deaths in 2020, worldwide
(Ferlay etal. 2021). Chemotherapeutic agents generally tar-
get the uncontrolled growth and proliferation of cancer cells
(Sak 2012).
Doxorubicin (DOX) is a chemotherapeutic agent from the
anthracyclines family, which is first extracted from Strep-
tomyces peucetius (Thorn etal. 2011). DOX acts against
cancer cells through multiple mechanisms, including (I)
intercalation into the DNA double helix and interference
with topoisomerase II-mediated DNA repair and (II) genera-
tion of free radicals which can damage cell membrane, DNA
molecules, and proteins. The latter mechanism is mediated
through oxidization of DOX to an unstable metabolite, semi-
quinone, which is then converted back to DOX in a process
that generate reactive oxygen species (ROS) (Thorn etal.
2011). Currently, DOX is routinely used for the treatment
of a wide range of human malignancies, such as acute leu-
kemia and lymphomas, carcinomas, sarcomas, breast, blad-
der, ovarian, gastric, bone, and also some pediatric cancers
(Kalyanaraman 2020). However, high doses and prolonged
use of this drug for cancer treatment are associated with
several side effects and post-treatment debacles, e.g., hepa-
totoxicity and cardiotoxicity, resulting in chemotherapy dis-
continuation or dose reduction (Shivakumar etal. 2012).
An increasing body of evidence demonstrates that differ-
ent synthetic drugs and naturally-occurring flavonoids may
be effective against DOX-induced hepatotoxicity. The ame-
liorative effects of such compounds include, but not limited
to the reduction of the inflammatory cytokines and oxida-
tive stress markers, down-regulation of pro-apoptotic pro-
teins and up-regulation of antiapoptotic proteins. These can
lead to reduction of liver enzymes serum level and hepatic
collagen fibers deposition scores (Superfin etal. 2007).
However, in spite of the extensive studies on the protective
effects of these compounds against DOX, the full potentials
and benefits and also the detailed mechanisms remain to
be elucidated. The objective of this study was to conduct a
review of published preclinical and clinical studies regarding
the protective effects of various herbal compounds against
DOX-induced liver injuries and to define the cellular and
molecular mechanisms underlying this hepatoprotection.
Materials andmethods
In May 2022, we explored scientific databases including
Embase, PubMed, and Scopus from the inception until now
with the following keywords: “doxorubicin,” “adriamycin,”
“hepatotoxicity,” “liver injury,” “liver damage,” and “hepato-
protective.” We considered no restriction on the availability
of the full text, if enough data could be accessed from the

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abstract. The Boolean operators and nesting were as follows:
(TS = (Doxorubicin) OR TS = (adriamycin)) AND (TS = (hepa-
totoxicity) OR TS = (“liver injury”) OR TS = (“liver damage”)
OR TS = (“liver toxicity”) OR TS = (hepatoprotective) OR
TS = (“liver dysfunction’) OR TS = (“drug-induced hepatitis”)
OR TS = (“fatty liver disease”) OR TS = (“liver failure”)). We
chose the related articles based on their title and abstract. Our
inclusion criteria were papers written in English that assessed
the protective effect of various herbal compounds against DOX-
induced hepatotoxicity. All invitro, invivo, and clinical studies
which were accordant with our criteria were included. Dupli-
cated or unrelated articles, or articles published in languages
other than English, were excluded, if they did not have English
abstract. Data collection was carried out between May 5, 2021
and April 15, 2022. The search process and initial selection
of eligible studies were done by the first author. Finally, in the
result section, we gathered and compared the effectiveness in
ameliorating DOX-induced hepatotoxicity.
Results
In present paper, 885 articles were found by searching
abovementioned databases. Among these articles, 647,
151, 23, 3, and 21 articles were omitted because of being
non-relevant, duplication, review articles, papers in other
languages, and using non-herbal compounds, respectively.
Finally, 40 studies were eligible for this review (Fig.2). The
included studies are summarized in Tables1 and 2. Thirty
compounds are assessed as hepatoprotective against DOX
and related studies are reviewed in the following sections.
Mechanisms ofdoxurobicin‑induced liver injury
A great deal of available studies on doxorubicin adverse
effects is focused on its cardiotoxicity. However, the admin-
istration of DOX is also frequently associated with toxic
injury to the liver and may intensify the rate of transient
increase in serum liver enzyme and acute liver injury with
jaundice that can be severe and even life-threatening (Dos
Santos Arruda etal. 2019). The production of ROS is the
major consequence of its redox cycling profile and is con-
sidered as a double-edged sword, which acts not only on
cancer cells but also on several normal body cells. Various
enzymes, including xanthine oxidases, NADPH oxidases,
nitric oxide synthases, and peroxidases, which are located
in several subcellular compartments, e.g., mitochondria,
endoplasmic reticulum, and cytoplasm, account as major
sources of ROS. These alterations may result in various
histopathological changes as well as induction of apoptosis
(Moher etal. 2009). The probable mechanisms of hepato-
toxicity are summarized in Fig.1. Furthermore, pharma-
cokinetics studies of DOX in patients with abnormal liver
biochemistry tests have discovered that patients with reduced
DOX clearance not only have an increased bilirubin level,
but also elevated levels of liver enzymes, such as aspartate
aminotransaminase (AST) and alanine aminotransaminase
(ALT) (Twelves etal. 1998). Approaches to doxorubicin
dosing in patients with impaired liver function are variable
now. The United States Prescribing Information for doxo-
rubicin and pegylated liposomal doxorubicin recommend a
50 percent dose reduction for bilirubin 1.2 to 3mg/dL, and
a 75 percent dose reduction for bilirubin 3.1 to 5mg/dL.
Others suggest omission of the drug for bilirubin > 5mg/dL
(Superfin etal. 2007; Sahlan etal 2021) (Fig.2).
Hepatoprotective effect ofherbal compounds
Citronellal
Citronellal is a well-known metabolite of Cymbopogon spp.
plants and is demonstrated to exhibit many beneficial prop-
erties such as insect repellent or antimicrobial activities (Wei
& Wee 2013). Given the various potentials of this drug in
health issues, Liu etal. investigated the effect of citronellal
(200mg/kg b.w./day orally) on DOX-induced hepatotoxic-
ity (2.5mg/kg b.w./week, intraperitoneally) in SD rats (Liu
etal. 2021). It attenuated DOX-induced pathological liver
tissue changes and improved liver function biomarkers.
In particular, citronellal administration resulted in signifi-
cant decrease in the levels of AST, ALT, glutamic pyruvic
transaminase, and albumin in serum and modulated the lev-
els of malondialdehyde, superoxide dismutase, and reduced
glutathione in liver. In addition, citronellal diminished the
Bax/Bcl-2 ratio and caspase-3 expression, thereby inhibiting
cell apoptosis. This drug also enhanced the levels of PI3K
signaling members and CD31 in the liver, further highlight-
ing the role of citronellal in the protection of liver against
DOX. So, it seems that anti-apoptosis and antioxidant activ-
ity is the most important proposed mechanism of action for
citronellal.
[10]‑Gingerol andginger extract
10-Gingerol is a member of gingerols, which are the major
pungent constituents in ginger (Zingiber officinale), and
comprises a series of homologues varying in the length
of their alkyl chains. 10-Gingerol is believed to inhibit the
anti-serotonin 3 receptor function leading to anti-emetic
properties (Semwal etal. 2015). In a study conducted by
Bapitsa etal. on 4T1Br4 murine TNBC cells bearing Balb/c
mice, concomitant use of 10-Gingerol (10mg/kg, five times
a week) and DOX (3mg/kg, twice a week) can increase
the levels of active caspase-3 and γH2AX and to decrease
the level of Cdk-6 cyclin (Baptista Moreno Martin etal.
2020). Likewise, combined regimen led to decreased tumor

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Table 1 Summarized hepatoprotective natural-occuring compounds against doxorubicin hepatotoxicity; preclinical studies
Study (year)
[reference]
Drug Type of study The way of administration and the dose of DOX Results/mechanisms
Liu etal. 2021 CTN In vivo 40 SD rats
4 groups:
CTRL: NS p.o
CTN: 200mg/kg/day p.o
DOX: 2.5mg/kg/week i.p
CT + DOX
6weeks
Sig ↓ liver histopathological changes
Sig ↑ serum ALB and sig ↓ serum levels of AST and ALT
Sig ↓ MDA levels and sig ↑ the hepatic levels of GSH and
SOD
Sig anti-apoptosis effect (↓ Bax/Bcl‐2 pr and caspase-3 pr
through activating PI3k/Akt signaling pathway)
Sig pro-angiogenesis effect (↑ CD-31 pr) in liver tissue
Baptista Moreno
Martin etal. 2020
G10 In vivo 60 4T1Br4 murine TNBC cells bearing Balb/c mice
4 groups:
CTRL: NS
G10: 10mg/kg 5times a week
DOX: 3mg/kg twice a week
G10 + DOX
28days
Sig ↑ BW in G10 + DOX group
Sig ↓ of survival rate in DOX group compared to others
Prevention of DOX-induced ↑ AST and ALT serum levels
Histological effect: ↓ liver inflammatory and liver damages
with G10 treatment
Sakr etal. 2007 GIN In vivo 60 albino rats
4 groups:
CTRL
DOX: 2mg/kg/week i.p
GIN: 24mg p.o. 3 times a week
DOX + GIN
6weeks
Sig ↑ in BW in DOX + GIN compared to DOX group
Sig ↓ in DOX-induced ALT, AST and MDA elevations
Sig ↑ in DOX-induced SOD reduction
Sig anti-inflammatory effects in treatment group
Ahmed etal. 2013 GIN In vivo 40 Albino Wistar rats
4 groups:
CTRL: NS p.o
GIN: 250mg/kg/day p.o
DOX: 2.5mg/kg for a total cumulative dose of 15mg/kg
DOX + GIN
14days
Sig offset of DOX-induced weight loss with GIN treatment
Sig ↓ DOX-induced severe liver damages, degeneration
and necrosis score, and hepatic collagen fibers deposi-
tion scores
Kocahan etal. 2017 QE In vivo 36 Wistar rats
6 groups: CTRL, QE, CPY, DOX, CPY + QE, DOX + QE
1.8mg/kg DOX i.p. once every 3weeks
10mg/kg QE i.p. daily
10weeks
Sig ↓ MDA levels in DOX + QE group
No sig changes in GSH levels
No sig differences in SOD levels
No sig changes in CAT levels
Sig ↑ GPx levels in the DOX group compared with
QE + DOX
Wang etal. 2012 QE In vivo Acute hepatotoxicity study on 24 C57BL/6 mice
4 groups:
CTRL: NS
DOX: 20mg/kg i.p. on day 5
QE: 100mg/kg/day p.o. for 4 consecutive days
DOX + QE
10days
Subchronic hepatic damages study on nude mice with SMMC7721
tumor xenografts: 4mg/kg/week DOX i.p. for 3weeks
Co-administration of DOX and QE: partial reversed of
DOX-induced ↑ of serum ALT and AST levels
Sig ↓ in liver histological damages in co-administration of
QE with DOX

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Table 1 (continued)
Study (year)
[reference]
Drug Type of study The way of administration and the dose of DOX Results/mechanisms
Ahmed etal. 2019 CSI and
EPI
In vivo 40 Wistar rats
4 groups:
CTRL: NS i.p. weekly and 1% CMC solution p.o. QOD
DOX: 4mg/kg i.p. weekly and 1% CMC solution p.o. QOD
DOX + CSI: DOX + 200mg/kg CSI p.o. QOD and 1% CMC solution
DOX + EPI: DOX + 25mg/5ml 1% CMC/kg EPI QOD
6weeks
CSI: sig ↓ in ALT, AST, ALP, GGT, AFP and total BL.
Non-sig ↑ serum ALB
EPI: sig ↓ in ALT, AST, ALP and AFP. Non-sig ↑ serum
ALB. Non-sig ↓ in total BL. Sig ↑ serum GGT activity
CSI: non-sig ↑ in SOD activity and sig ↓ LPO
EPI: sig ↑ in SOD activity and sig ↓ LPO
Sig ↑ in hepatic GSH and GPx activity with both CSI and
EPI. Non-sig effect on GST
Sig ↓ in p53 mRNA expression, ↑Bcl2 mRNA expression
and ↓liver NF-κB mRNA expression with both CSI and
EPI
Sig amelioration of DOX-induced liver histological injuri-
ous alterations with both CSI and EPI treatments
Feeble expression of COX-2 and caspase-3 with both CSI
and EPI treatments
Kalender etal. 2005 VitE and
CTH
In vivo 38 SD rats
6 groups:
CTRL: 1ml/week water i.v
DOX: 5mg/kg/week i.v
VitE: 200IU/kg/week i.v
CTH: 200mg/kg/week i.p
VitE + DOX
CTH + DOX:
Non-sig difference in SOD activity between DOX,
VitE + DOX and CTH + DOX groups
Sig ↓ in GPx, CAT, MDA activity in VitE + DOX and
CTH + DOX groups compared to the DOX group
Sig amelioration of hepatocyte changes in VitE + DOX
and CTH + DOX groups compared with DOX group
Somparn etal. 2015 CUR or
THC
In vitro HeLa (Chang liver) cells
CUR or THC 1 or 6μM for 24h
Sig. ↑ in cell survival to 80 or 90%, respectively with THC
or CUR (p < 0.05)
Associated with suppressed DOX superoxide formation
and induction of GCLC and NQO1 expression
Yenny etal. 2020 CURL and
VCO
In vivo 15 Wistar rats
5 groups:
CTRL: Na-CMC
DOX: 5mg/kg/week
DOX + VCO: DOX + 6ml VCO
DOX + CURL: DOX + 100mg/kg CURL
VCO + CURL + DOX:
3weeks
Sig ↓ in ALT and AST levels in all treated groups
CURL + DOX was more effective than VCO + DOX
Lowest ALT and AST levels in VCO + CURL + DOX
group
Prevention of DOX-induced production of blood lipid
peroxides in rat liver by secondary metabolites of VCO
(flavonoids and phenolics) with antioxidant features
Neutralization of superoxide radicals with antioxidant
effects of curcuminoid compounds in CURL
Khazdair etal. 2016 CUR and
vit C
In vivo 48 male Wistar rat
6 groups (n = 8):
CTRL: 0.5ml NS IV on day 1
DOX: 5mg/kg IV on day 1
Vit C: 100mg/kg in drinking water for 28 consecutive days
DOX + vit C
CUR: 1000mg/kg in drinking water for 28 consecutive days
CUR + DOX
Sig ↓ in DOX-induced MDA elevation in DOX + CUR or
Vit C groups
Sig ↑ in DOX induced reduction of CAT activity in liver in
Vit C + DOX group but not CUR group
No sig. changes in thiol level by co-administration of CUR
or Vit C

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Table 1 (continued)
Study (year)
[reference]
Drug Type of study The way of administration and the dose of DOX Results/mechanisms
Mohebbati etal. 2017 CUR, vit
C and
Nigella
sativa
In vivo 64 male Wistar rat
8 groups (n = 8):
CTRL: 0.5ml NS IV on day 1
DOX: 5mg/kg IV on day 1
Vit C: 100mg/kg in drinking water for 28 consecutive days
DOX + vit C
CUR: 1000mg/kg in drinking water for 28 consecutive days
CUR + DOX
Nigella sativa 200mg/kg in drinking water for 28 consecutive days
Nigella sativa + DOX
Sig ↓ in DOX-induced MDA elevation in DOX + Vit C
group
Sig ↑ in DOX induced reduction of CAT activity and thiol
level in liver in Vit C + DOX and CUR + DOX groups
(in Nigella sativa group, just for CAT activity)
Sadat-Hoseini and DabidiRoshan
2017
Nano-
CUR
In vivo Male Wistar rat
10 groups (n = 8)
DOX 1mg/mL/kg/day, i.p. for 15d, Nanomicellar curcumin soft
gels (Sinacurcumin ®) 100mg/kg gavage for 14days
Insig. ↑ in DOX-induced reduction of SOD and also on
apoptosis induing factors
Lalmuansangi etal. 2020 GAP In vivo 42 DLA bearing swiss albino mice (except CTRL group)
7 groups:
CTRL: 0.5ml NS i.p. on day 1
DLA: 0.5ml NS i.p. on day 1 + 0.5ml/day 1% ethanol p.o
DOX: 20mg/kg i.p. on day 1 + 0.5ml/day vehicle p.o
DOX + GAP: DOX + GAP at a dosage of 50, 100 and 150mg/kg
respectively p.o. daily
GAP: 0.5ml NS i.p. on day 1 + 100mg/kg/day GAP p.o
Sig ↓ in ALT, AST and LDH in DOX + GAP (150mg/kg)
Sig ↑ DOX-induced reduction of antioxidant parameters
levels (GSH, GST, CAT and SOD) in DOX + GAP
groups treated for 7days
Dose-dependent hepatoprotective effect of GAP
Sig ↓ in DOX-induced MDA elevation in DOX + GAP
groups with different doses
Zhao etal. 2012 BRB In vivo 40 mice
4 groups:
CTRL: 10mg/kg NS i.p. QOD
DOX: 2.5mg/kg i.p. QOD
DOX + BRB: 60mg/kg BRB i.p. 1h before DOX
BRB: 60mg/kg i.p. QOD
14days
Sig ↓ in BW in DOX compared to CTRL, BRB and
BRB + DOX groups
Sig ↑ liver weight in BRB + DOX compared to DOX
group
↓ in mortality rates in DOX and BRB + DOX groups
respectively
Sig ↓ DOX-induced ALT and AST elevations in
BRB + DOX group; hence, efficient protection against
hepatotoxicity
Sig prevention of DOX-induced hepatic injuries and
inflammation

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Table 1 (continued)
Study (year)
[reference]
Drug Type of study The way of administration and the dose of DOX Results/mechanisms
Patel etal. 2010 SMN In vivo Male ICR mice
4 groups
CTRL: NS i.p. daily
DOX: 60mg/kg DOX (LD50) on day 12 + NS i.p daily
SMN: 16mg/kg/day p.o
DOX + SMN
-14days
↑ in BW in DOX + SMN group
Sig ↓ in mortality rate in DOX + SMN group
Sig ↓ in DOX-induced elevation of serum ALT level in
DOX + SMN
Sig ↓ in liver histopathological changes in DOX + SMN
group
Sig prevention of DOX-induced oxidative stress (↓ MDA
levels) in DOX + SMN group
Sig ↓ in DOX-induced liver DNA fragmentation due to
blocked DOX-mediated initiation of caspase-activated
DNAse in DOX + SMN group
Sig amelioration of DOX-induced ↓ Bcl-xL and ↑ PARP in
SMN + DOX group
Little effect of SMN pre-treatment on DOX-induced ↑ P53
Sig ↓ in DOX- induced increase of DNA cleavage with
SMN pre-treatment
Rašković etal. 2011 SMN In vivo 30 Wistar rats
5 groups:
CTRLS: 1ml/kg p.o
CTRL: 1ml/kg olive oil p.o
SMN: 60mg/kg/day p.o
DOX: 1.66mg/kg i.p. QOD
DOX + SMN
12days
Sig ↑ in BW in DOX + SMN group
Sig ↓ in DOX-induced LPO in DOX + SMN group
Sig ↑ in XOD, CAT and GPx activities in DOX group
No sig changes in GSH level in DOX + SMN group
Sig ↓ in AST and LDH levels in DOX + SMN group. No
sig changes in ALT levels
Sig protection against DOX-induced histopathological
alterations
Abbas etal. 2020 SMN and
CGA
In vivo 30 albino rats
5 groups:
CTRL: 0.5ml/kg NS i.p
DOX: 1.5mg/kg i.p. QOD
SMN: 1.5mg/kg DOX i.p. QOD + 206.7mg/kg SMN p.o. QOD
CGA: 1.5mg/kg DOX i.p. QOD + 124mg/kg CGA p.o. QOD
SMN + CGA: DOX + SMN + CGA
Sig ↓ liver enzyme activities (AST, ALT and GGT) in
SMN and SMN + CGA than CGA group. More statisti-
cally sig ↓ enzymes activities in SMN + CGA group
Sig ↓ in DOX-induced caspase-3 elevation in SMN and
CGA groups. More statistically sig ↓ caspase-3 and
NF-kB levels in SMN + CGA group
Sig ↑ in P-AKt level in SMN and SMN + CGA groups in
comparison with DOX and CGA groups
Sig ↓ in MDA level and sig ↑ SOD and AMPK levels in
SMN and CGA groups compared to DOX. More statisti-
cally sig amelioration of MDA, SOD and AMPK in
SMN + CGA group compared to others
Sig ↑ in hepatic inflammatory reactions (TNF α and IL-1β)
in CGA compared to CTRL group
Sig ↓ in inflammatory reactions in SMN group; more sig
↓ TNF α and IL-1β in SMN + CGA group compared to
each one individually

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Table 1 (continued)
Study (year)
[reference]
Drug Type of study The way of administration and the dose of DOX Results/mechanisms
Barakat etal. 2018 BOS In vivo 40 Swiss albino mice
5 groups:
CTRL: 16mg/kg/week NS i.p. and 12ml/kg/day water p.o
DOX: 6mg/kg/week i.p. + water p.o
BOS125: 125mg/kg/day BOS p.o. + DOX
BOS250: 250mg/kg/day BOS p.o. + DOX
BOS500: 500mg/kg/day BOS p.o. + DOX
3weeks
Sig ↓ in ALT and AST in a dose-dependent manner
Sig ↓ in MDA levels in all BOS treated groups
Sig ↑ in expression of NRF-2 and HO-1 in a dose-depend-
ent manner
Sig ↓ in expression of caspase-3 in a dose-dependent
manner
Sig ↓ in apoptosis and DNA fragmentations in BOS
treated groups
Sig ↓ in DOX-induced histopathological changes in a
dose-dependent manner
Song etal. 2019 DIS In vitro and
invivo
In vitro: AML-12 cells + DIS (50, 100 and 200ng/ml) 6, 12 and
24h before DOX treatment (5ng/ml) for 24h
In vivo: 40 male mice
5 groups:
CTRL: 0.5% Na-CMC
DOX: 15mg/kg i.p. on the 7th day
DIS60: 60mg/kg DIS p.o. + DOX
DIS30: 30mg/kg DIS + DOX
DIS15: 15mg/kg DIS + DOX
14days
Sig protection of DOX-induced cell injuries in a dose- and
time-dependent manner
Sig reverse of DOX-induced morphological changes
invitro and invivo experiments
Sig ↓ in ALT and AST levels
Sig ↓ in oxidative stress (↓ ROS and MDA levels)
Sig ↑ in antioxidant parameters (GSH, GPx and SOD
levels)
Sig ↓ in DOX-induced apoptosis invitro and invivo
experiments (↓ TUNEL positive cells)
Sig ↑ in pr levels of NRF-2 and HO-1 and ↓ pr levels of
FOXO1 and Keap1 invitro and invivo studies
Sig ↓ in DOX-induced inflammation (↓ expression of
NF-kB and mRNA levels of IL-1β, IL-6 and TNF-α)
invitro and vivo experiments
Sig ↓ in expression levels of P53 and Bax and ↑ Bcl -2 in a
dose dependent manner
Sig ↓ in oxidative stress, inflammation and apoptosis via ↑
Sirt 1 expression levels
Jung etal. 2014 EDI In vitro Hepatocytes isolated from SD rats
Adding 10µl of 5µM DOX to each well and 2days incubation
Sig protective effects of EtOAc and n-BuOH fractions of
EtOH extract of EDI with EC50 values of 3.0µg/ml and
8.4µg/ml respectively as compared with positive CTRL
SMN (EC50 value = 8.0µg/ml)
Concurrent cytotoxic effects at hepatoprotective concen-
tration observed with CH2Cl2 fraction
No sig protective effects observed in n-hexane and H2O
fractions
Sig protective effect of EtOAc fraction’s plorotanins
respectively:
dioxinodehydroeckol > phlorophucophuroeckol
A > dieckol > eckol > triphloroethol-A

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Table 1 (continued)
Study (year)
[reference]
Drug Type of study The way of administration and the dose of DOX Results/mechanisms
Rashid etal. 2013 CH In vivo 30 Wistar rats
5 groups:
Negative CTRL: 10mg/kg/day corn oil and NS single i.p
Positive CTRL: 40mg/kg DOX i.p. on day 14
DOX + CH40: 40mg/kg/day CH p.o. + DOX
DOX + CH80: 80mg/kg/day CH p.o. + DOX
CH: 80mg/kg/day p.o
16days
Sig ↓ of DOX-induced hepatic toxicity markers (serum
ALT, AST and LDH activities) with CH treatment at
both doses
Sig ↑ of DOX-induced reduction of hepatic GSH levels in
CH treatment with both doses
Sig ↑ of DOX-induced reduction of hepatic antioxidant
enzymes (GPx, GR, CAT and SOD) in CH pre- and
post-treatment
Sig ↓ of MDA formation by mending membrane integrity
and ↓ DOX-induced LPO in DOX + CH treatments
CH pre-treatments retained the structure of liver cells near
to that of CTRL group
Liu etal. 2017 NIN In vitro and
invivo
In vitro: Hela cells seeded on a 96-well plate and then added 20µl
of DOX (1.6 to 10.0µg mL−1) and NIN (200 to 2000µmol L−1)
at different concentrations
In vivo: 32 Hela cells bearing athymic nude mice
4 groups: CTRL: NS; DOX: 5mg/kg; NIN: 20mg/kg;
DOX + NIN
DOX and NIN administration with 3-day interval for 5 times
Sig anti-tumor efficacy in DOX + NIN group compared to
DOX and NIN groups invitro and invivo
Sig ↓ in DOX-induced weight loss and systemic sides
effects in DOX + NIN group
Sig ↓ in hepatocyte necrosis in DOX + NIN compared to
DOX group
Wali etal. 2020 NIGN In vivo 24 Wistar rats
4 groups:
CTRL: vehicle p.o. daily
DOX: 20mg/kg i.p. on the 20th day
NIGN50: 50mg/kg/day NIGN p.o. + DOX
NIGN100: 100mg/kg/day NIGN p.o. + DOX
20days
Sig ↓ in oxidative stress (↓ROS and MDA levels)
Sig ↑ in antioxidant enzymes (GSH, GPx, GR, SOD and
CAT) in NIGN treatments in a dose dependent manner
Sig ↓ of H2O2 in liver tissue
Sig ↓ in DOX-induced ↑ serum toxicity markers (ALT,
AST, ALP, LDH and total pr)
Sig ↓ in inflammatory mediators (NF-kB, TNF-α, IL-1β,
PGE-2, TGF-β and IL-6)
Sig ↓ in DOX-induced elevated NO levels
Sig protection of DOX-induced liver damages in NIGN
treatment at higher dose
Sig ↓ in expression of COX-2 in NIGN treatments con-
cludes anti-inflammatory potential of NIGN
Anandakumar etal. 2007 LA In vivo 24 Wistar rats
4 groups:
CTRL: NS
DOX: 15mg/kg DOX single injection i.p
LA: 75mg/kg LA single injection i.p
DOX + LA: single injection of LA 24h before DOX
4days
Sig ↓ of DOX-induced elevation of serum enzymes (ALT,
AST and BL) and Sig ↑ of DOX-induced reduction of
liver enzymes (ALP, LDH, AST and ALT) in DOX + LA
group
Sig ↓of lipid per-oxidations (basal, ascorbate and ferrous-
sulfate-induced) in DOX + LA group
Sig ↑ of antioxidants (GSH, CAT, SOD, GPx, GR, GST
and G6PD) in DOX + LA group

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Table 1 (continued)
Study (year)
[reference]
Drug Type of study The way of administration and the dose of DOX Results/mechanisms
Mokni etal. 2015 GSSE In vivo 24 Wistar rats
4 groups:
1.CTRL: ethanol i.p
2. GSSE: 500mg/kg/day i.p
3. DOX: 20mg/kg single i.p. on day 4 till day 8
4. DOX + GSSE
8days
Sig ↓ in DOX-induced increase of AST and ALT levels
Sig ↓ in MDA level and pro-oxidative effect of DOX in
DOX + GSSE group
Sig amelioration of DOX-induced liver antioxidant
enzymes alterations (↓CAT, ↑POD and ↑SOD) in GSSE
pre- and post-treatment
Sig restore of DOX-induced intracellular mediator disor-
ders (↓ free Fe, ↓H2O2 and ↑Ca) nearly to CTRL levels
Sig protection of liver structure against DOX-induced liver
damages
Aktaş etal. 2020 ATS In vivo 49 SD rats
7 groups:
1.CTRL: untreated
2. DOX: 10mg/kg single i.p. on first day
3.DOX + ATS7: DOX + 7mg/kg/day ATS p.o
4. DOX + ATS35: DOX + 35mg/kg/day ATS p.o
5. Negative CTRL: 1ml/kg/day NS p.o
14days
Sig ↑ in liver degenerative changes and histological score
in DOX group
Caspase-3 and ↑ expression of TNF-α in hepatocytes in
DOX group; no expression in other groups
↑ expression of iNOS in DOX group and ↓ in
DOX + ATS7 group; no expression in other groups
↑ NF-kB expression in DOX group and ↓ in ATS treat-
ments with either dose
Kuzu etal. 2019 Morin In vivo 35 Wistar albino rats
5 groups:
CTRL: NS p.o. + NS i.p. on the 8th day
Morin: 100mg/kg/day p.o + NS i.p. on the 8th day
DOX + morin50: 40mg/kg DOX single i.p. on the 8th day + 50mg/
kg/day morin
DOX + morin100
10days
Sig ↓ in MDA levels in morin pre-treatment groups in a
dose dependent manner
Sig ↑ in antioxidant markers (SOD, CAT and GPx)
Sig improving of liver function by ↓ ALT and AST activi-
ties
Sig regulatory effect on TNF-α, IL-1β and NF-κB levels
Sig anti-apoptotic effect ↑ Bcl-2 level and ↓ Bax level in a
dose dependent manner
Sig preservation of liver structure against DOX damages
in DOX + morin100 group
Ma etal. 2020 ATX In vivo 30 ICR mice
5 groups:
CTRL: 6mg/kg NS i.p
DOX: 6mg/kg single i.p
Solvent: DOX + 50mg/kg/day corn oil
ATX50: DOX + 50mg/k/day ATX
ATX100: DOX + 100mg/k/day ATX
3weeks
Sig ↑ in BW and food intake in ATX groups compared to
DOX group
Sig ↑ in liver function by ↓ DOX-induced elevation of
ALT, AST, ALP and total BL in ATX groups with either
doses
Sig preservation of hepatocytes against DOX-induced
injuries
Sig anti-apoptosis features of ATX treatments with both
doses
Sig ↑ in antioxidant markers levels (SOD, CAT and GPx)
in ATX groups
Sig ↓ in ROS and MDA levels in ATX groups

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Table 1 (continued)
Study (year)
[reference]
Drug Type of study The way of administration and the dose of DOX Results/mechanisms
Kamble and Patil 2018 AA In vivo 36 Wistar rats
6 groups:
CTRL: 1ml/day NS
STD: 200mg/kg VitE p.o
DOX: 65.75mg/kg i.v
AA5: 5mg/kg/day p.o
AA10: 10mg/kg/day p.o
AA20: 20mg/kg/day p.o
DOX administration in all groups (except CTRL) 48h before the
end of study
7days
Sig ↓ in DOX-induced upsurge of injury marker enzymes
(LDH, ALT and AST)
Sig ↑ in antioxidant markers (SOD and GSH) in AA20
group
Sig ↓ in DOX-induced elevation of LPO in AA20 group
Sig protection of liver architecture against DOX-induced
alterations
Roomi etal. 2014 NM In vivo 24 Balb/c mice
4 groups:
CTRL: RCD
NM: RCD + 20mg/day NM
DOX: RCD for 3weeks prior to 20mg/kg DOX i.p
DOX + NM: RCD + DOX + NM
3weeks
No sig effect of DOX on liver weight in both groups
Sig ↑ in food intake in mice treated with NM
Sig protection of liver function against DOX-induced ↑
serum enzyme levels (ALT, AST and GGT)
Afsar etal. 2019 AHE In vivo 36 SD rats
6 groups:
CTRL: 0.4ml/week NS i.p
DOX: 3mg/kg/week i.p
AHE: 400mg/kg/day p.o
DOX + AHE200
DOX + AHE400
DOX + SMN: DOX + 100mg/kg SMN 2 times a week
6weeks
Sig amelioration of DOX-induced ↓BW and ↑ liver weight
with AHE treatments in a dose dependent manner
Sig ↓ in ALT, AST, ALP, LDH, total and direct BL with
AHE treatments in a dose dependent manner
Sig ↓ in chol, TG and LDL with AHE treatments
Sig ↑ in HDL in DOX + AHE400 group
Sig ↑ in antioxidant parameters levels (POD, SOD, CAT,
QR, GSH, GR, GST, GGT and GPx) with AHE treat-
ments dose dependently
Sig ↓ in oxidative stress markers (H2O2 and NO) and LPO
(TBARs) with AHE treatments dose dependently
Sig ↓ in DOX-induced liver injuries with AHE high dose
Rafiee etal. 2021 pCA In vivo 32 Wistar rats
4 groups:
CTRL: 10% PG p.o
pCA: 100mg/kg/day p.o
DOX: 15mg/kg i.p. on day 5
DOX + pCA
5days
Sig ↓ in serum ALT, AST, ALP, TG, chol, LDL, and total
BL and sig ↓ in HDL and serum ALB with pCA treat-
ment
Sig ↓ in LPO (MDA) and sig ↑ antioxidant enzymes
activities (GPx, SOD and CAT)
Sig prevention of DOX-induced liver histopathological
changes
Sig ↓ in IL-1β expressions in liver tissues
Khajavi Rad 2021 ZJ In vivo Wistar rats
5groups: CTRL, DOX and 3 orally doses of ZJ
1month
Sig ↓ in ALT, AST, LDH, ALP, total and direct BL
Sig ↓ in oxidative stress

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Table 1 (continued)
Study (year)
[reference]
Drug Type of study The way of administration and the dose of DOX Results/mechanisms
Husna etal. 2022 MNG In vivo 25 SD rats
5 groups:
Normal: corn oil and NaCl 0.9% QOD fo 2weeks
DOX: 2.5mg/kg DOX QOD for 2weeks
MNG50: DOX + 50mg/kg MNG PO for 5weeks
MNG100: DOX + 100mg/kg MNG PO for 5weeks
Positive CTRL: DOX (2weeks) + 50mg/kg SMN (5weeks)
Sig ↓ in ALT and AST in MNG50 and 100 groups
Sig ↓ in MDA level and sig ↑ GSH and SOD in MNG50
and 100 groups
Slight liver damage in MNG goups compared to DOX
group (not assessed statistically
Improvement of liver function and oxidative stress with
MNG treatment
Ahmed etal. 2022 TYM and
TML
In vivo 24 wistar rats
4 groups:
Normal: 0.9% NaCl 1ml/kg i.p. every week
+ 1% CMC 5ml/kg QD p.o. for 7weeks
DOX: 2mg/kg i.p. every week + 1% CMC p.o. QOD for 7weeks
TYM: 2mg/kg DOX i.p. every week + 250mg TYM p.o. QOD for
7weeks
TML: 2mg/kg DOX QOD + 100mg TML p.o. QOD for 7weeks
Sig ↓ in DOX induced elevated AST, ALT, ALP and total
BL in TML group
Distinguished but non-sig ↑ ALB level in TYM group
(TML more effective in ameliorating liver function than
TYM exception for ALB level)
Sig ↓ in AFP and CA19.9 (tumor marker), serum TNFα
and IL-4 in both treated groups (TYM more effective)
Sig ↓ in LPO and ↑ GSH and activities GST and GPx
Sig ↑ in DOX-induced reduction of Bcl-2 mRNA expres-
sion (TML more effective)
Sig ↓ in liver p53 expression
Sig ↓ in liver histopathological changes including inflam-
mation, apoptosis and fibrosis
Improvement of liver function, inflammation, oxidative
stress, apoptosis, and liver structure
Mohebbati etal. 2018 ZM and
CAR
In vivo 24 wistar rats
4 groups:
Normal: 0.9% NaCl
DOX: 5mg/kg IV 28 d + NS
DOX + ZM: 200mg/kg IV 28 d
DOX + CAR: 20mg/kg IV 28 d
Sig. ↓ in serum ALP, ALT and AST in ZM and CAR
groups compared to those of the ADR group
Sig. ↓ in MDA in ZM and CAR groups compared to those
of the ADR group
Sig ↑ in CAT activity in ZM and CAR groups compared to
those of the ADR group
Sig ↑ in thiol levels in ZM group compared to the ADR group
CTN, citronellal; SD, Sprague–Dawley; CTRL, control; NS, normal saline; p.o., orally; DOX, doxorubicin; i.p., intraperitoneal; sig, significant; ALB, albumin; AST, aspartate aminotransferase;
ALT, alanine aminotransferase; MDA, malondialdehyde; GSH, glutathione; SOD, superoxide dismutase; Bax, Bcl-2 associated X protein; Bcl-2, B-cell lymphoma 2; pr, protein; PI3k, phospho-
inositide 3-kinase; Akt, protein kinase B; G10, [10]-Gingerol; TNBC, triple negative breast cancer; GIN, Zingiber officinale; QE, quercetin; GPx, glutathione peroxidase; CSI, Camellia sinensis;
EPI, epicatechin; CMC, carboxymethyl cellulose; QOD, every other day; GGT , Gamma-glutamyl transferase; AFP, alpha-fetopotein; BL, bilirubin; LPO, lipid peroxidation; GST, glutathione-
S-transferase; NF-kB, nuclear factor-kappa B cells; COX-2, cyclooxygenase-2; VitE, vitamin E; CTH, catechin; CUR , curcumin; THC, tetrahydrocurcumin; GCLC, glutamylcysteine ligase cata-
lytic subunit; NQO1: NADP (H), quinone oxidoreductase1; CURL, Curcuma longa; VCO, virgin coconut oil; Na-CMC, sodium carboxymethyl cellulose; GAP, Ganoderma applantum; DLA,
Dalton’s lymphoma ascites; BRB, berberine; SMN, silymarin; Bcl-xL, B-cell lymphoma-extra large; PARP, poly-ADP-ribose polymerase; P53, tumor protin P53; XOD, xanthine oxidase; CGA
,chlorgenic acid; P-AKt, protein kinase B; AMPK, AMP-activated protein kinase; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; BOS, boswellic acid; NRF-2, nuclear factor erythroid2-
related factor 2; HO-1, heme oxygenase 1; DIS, dioscin; AML-12 cells, alpha mouse liver 12 cells; ROS, reduced reactive oxygen species; TUNEL, terminal deoxynucleotidyl transferase dUTP
nick end labeling; FOXO1, forkhead box rotein O1; keap1, kelch like ECH associated protein 1; IL-6, interleukin-6; EDI, edible brown alga Ecklonia stolonifera; CH, chrysin; Cr, creatine; STD,
standard; FN-1, fibronectin; 8-OHdG, 8-hydroxydeoxyguanosine; MCP-1, chemoattractant protein-1; NIN, naringin; NIGN, naringenin; PGE-2, prostaglandin-E2; TGF-β, transforming growth
factor beta; LA, DL-alpha lipoic acid; G6PD, glucose-6-phosphate dehydrogenase; GSSE, grape seed and skin extract; POD, peroxidase; ATS, artemisinin; ATX, astaxanthin; AA, asiatic acid;
NM, nutrient mixture; RCD, regular chow diet; ZM, zataria multiflora; CAR , carvecrol; AHE, acacia hydaspica; QR, quinone reductase; pCA, p-coumaric acid; ZJ, Ziziphus jujuba; EXR, short
term exercise; NrF-1, nuclear respiratory factor 1; HSP70, heat shock protein 70; Sirt1, sirtuin 1; AIR, regular aerobic training; IGF-1, insulin-like growth factor-1; IGFBP-3, insulin-like growth
factor binding protein-3; MNG, mangiferin; TYM, thyme oil; TML, thymolol

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dissemination and inhibited chemotherapy-induced weight
loss and hepatotoxicity. The combination of these drugs also
resulted in decreasing the numbers of circulating tumor cells
in the peripheral blood of the tumor-bearing animals.
In addition, two other studies evaluated the hepatoprotec-
tive effects of aqueous extract of ginger on DOX in albino
Wistar rats. In the first study, Sakr etal. mentioned that adri-
amycin (2mg/kg/w) induced various histological changes in
the liver and significantly increased the serum levels of ALT
and AST after 4 and 6weeks of treatment. It also caused an
increase in malondialdehyde (lipid peroxidation marker) and
depletion of the antioxidant enzyme; superoxide dismutase.
On the other hand, treatment of the rats with aqueous extract
of ginger (24mg/kg thrice weekly for 6weeks) beside adria-
mycin led to histological and functional improvement of the
liver. The ginger extract also reduced the level of malon-
dialdehyde and increased the activity of superoxide dis-
mutase. In the second study, Ahmed etal. also showed that
adriamycin (2.5mg/kg/d) resulted in the destruction of the
hepatic cords and adverse pathological changes in the liver
of animals. However, these hepatotoxic effects were par-
tially ameliorated when treatment was combined with ginger
(250mg/kg/d) for 2weeks (Ahmed etal. 2013). Moreover,
considering the dose of ginger and DOX in two abovemen-
tioned studies, it seems that the protective effect of ginger is
dose dependent, and the cumulative dose of both ginger and
DOX is almost similar in both studies. So, gingerol possess
antioxidant and anti-inflammatory features and can prevent
the liver damage by these mechanisms.
Quercetin
Quercetin is a flavonoid which is found in several fruits and
vegetables and receives an increasing attention as an anti-
oxidant and a pro-apoptotic flavonoid. Two invitro studies
have evaluated its hepatoprotective role against DOX. The
first study was conducted by Wang etal. on liver in C57BL/6
mice. Their investigations, using the MTT and Annexin V/
PI staining assay, revealed that that quercetin (100mg/kg/d
4days) significantly stimulated the cytotoxicity of DOX
Table 2 Summarized hepatoprotective natural-occuring compounds against doxorubicin hepatotoxicity; clinical studies
CAF, cyclophosphamide 600mg/m2 + doxorubicin 60 mg/m2 + 5-FU 600 mg/m2; TB, total bilirubin; RCT, randomized clinical-trial; AC-T regi-
men: doxorubicin, cyclophosphamide, and paclitaxel regimen; CPY, cyclophosphamide; DOX, doxorubicin
Combination Type of study Subject Dose Result Ref
SMN/CAF Open label RCT 74 patients with breast
cancer
Treatment group 1
(n = 25): 210mg/d
SMN
Treatment group 2
(m = 25): 420mg/d
SMN
Control group
(n = 24): no inter-
vention
for three course of
21days
-Sig. elevation of AST
and ALT in group
1, sig. reduction
with SMN, in a time
and dose dependent
manner
-No sig. change in TB
after treatment with
SMN
Mshemish etal. (2011)
SMN / DOX, epi-
rubicin, CPY, and
taxanes
placebo-controlled
RCT
99 patients with
invasive breast
carcinoma
Study group (n = 49):
70mg (Livergol®)
PO three times daily
Control group
(n = 50): Placebo
-Sig. lower increase
in AST ad ALT in
treatment group
Mohaghegh etal.
(2015)
SMN /AC-T Triple blind, placebo-
controlled RCT
30 breast cancer
patients who
received AC-T
regimen
Treatment group
(n = 15): 140mg
(Livergol®) three
times a day for
1month
Placebo group (n = 15)
- Non-sig trend
toward more severe
liver involvement in
placebo group based
on ultrasonography
- Sig. hepatic involve-
ment grade improve-
ment based on
ultrasonography in
treatment group
-No sig. different
between two groups
based on FibroScan
and liver function
tests
Askarpour etal.2021

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Fig. 1 Probable mechanisms of doxorubicin induced hepatotoxicity
Fig. 2 Diagram of the study
selection process

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(20mg/kg on day 5) in liver cancer cells while protecting
normal liver cells. This pro-apoptotic effect on hepatoma
cells was p53-dependent and occurred by downregulating
Bcl-xl expression. Moreover, quercetin reversed the DOX-
induced pathological changes and decreased the serum lev-
els of ALT and AST (Wang etal. 2012).
In the other study, Kocahan etal. evaluated the effects
of quercetin (10mg/kg/day) on doxorubicin (1.8mg/kg IP
every 3weeks, for 10weeks) (Kocahan etal. 2017). Querce-
tin diminished the DOX-induced production of malondial-
dehyde and also increased glutathione peroxidase levels. So,
it seems that quercetin with anti-apoptotic and antioxidant
activity can be effective for prevention of DOX liver injury.
Vitamin E, catechin, epicatechin, andgreen tea
Vitamin E is an antioxidant with endogenous origin which
can suppress the propagation of lipid peroxidation and is
helpful in scavenging free radicals. Catechin is a type of
natural phenols with abundant antioxidant activity and is
a plant secondary metabolite, belonging to the group of
flavan-3-ols. Kalender etal. showed promising hepatopro-
tective effects of vitamin E (200IU/kg/week) and catechin
(200mg/kg/week) in SD rats against DOX (5mg/kg/week)
by obtaining the maximum levels of glutathione peroxidase
(Kalender etal. 2005), whereas malondialdehyde levels
considerably decreased in both vitamin E + DOX and cate-
chin + DOX groups. Electron microscopic studies supported
biochemical hepatoprotective findings.
Also, Ahmed etal.’s treatment of DOX-injected Wistar
rats (4mg/kg i.p. weekly) with aqueous extracts of Camel-
lia sinensis (green tea) leaf (200mg/kg) and epicatechin
(25mg/kg) resulted in significant correction of albumin,
alpha-fetoprotein, bilirubin, ALT, AST, alkaline phos-
phatase, and gamma glutamyl transferase (GGT) levels. The
treatments also diminished the serum levels of tumor necro-
sis factor (TNF)-α and interleukin-4, liver lipid peroxidation,
and glutathione levels as well as liver superoxide dismutase,
glutathione peroxidase, and glutathione-S-transferase activi-
ties. The expressions of liver nuclear factor-kappa B cells,
p53, and caspase-3 were also highly decreased, whereas the
expression of Bcl-2 was increased, and the liver histologi-
cal architecture was remarkably ameliorated. The authors
concluded that Camellia sinensis aqueous extract and epi-
catechin may have great hepatoprotective effects against
DOX which seems to be through reinforcement of antioxi-
dant defense system and attenuation of the inflammation and
apoptosis (Ahmed etal. 2019).
In another study, Roomi etal. evaluated the preventive
effect of a unique nutrient mixture (NM) (20mg/kg), contain-
ing primarily ascorbic acid, lysine, proline, N-acetyl cysteine,
and green tea extract against adriamycin (20mg/kg)-induced
hepatic and renal toxicity in male BALB/c mice. This extract
exhibits a broad spectrum of pharmacological activities,
including antioxidant activity. NM significantly increased
food intake in the mice and significantly protected the liver
function against DOX-induced elevation of serum liver
enzyme levels (ALT, AST, and GGT) (Roomi etal. 2014).
Curcumin
Curcumin (CUR) is a natural antioxidant agent which is
nontoxic even up to 12g/day based on human clinical trials.
Various studies focused on CUR antioxidant, anti-inflam-
matory, and anti-tumor activities. This bioactive molecule
is isolated from the rhizomes of Curcuma longa (turmeric).
Lots of studies have highlighted the role of CUR in inhibi-
tion of ROS generation in numerous cell lines and organ tis-
sues of animals and shown beneficial effects in management
of different DOX-induced toxicity including heart, CNS,
kidney, and liver. Moreover, it is proposed that curcumin
may suppress tumor growth, by scavenging free radicals and
inhibiting ABC drug transporters which bring it up as a host
of research studies for improving chemotherapeutic agents’
efficacy (Mohajeri & Sahebkar 2017). Regarding its hepato-
protective effects against DOX, several invitro and invivo
researches are available. An invitro study on Chang liver
cells, pre-treatment with tetrahydrocurcumin or CUR (1 or
6μM) for 24h significantly increased cell survival to 80 and
90%, respectively via suppression of DOX-induced superox-
ide formation and induction of lutamylcysteine ligase cata-
lytic subunit (GCLC) and NADP (H): quinone oxidoreduc-
tase1 (NQO1) expression (Somparn etal. 2015). In Khazdair
etal.’s study, Curcuma longa in dose of 1000mg/kg PO
for 28 consecutive days could be protective against hepa-
totoxicity induced by DOX 5mg/kg in rats, via antioxidant
mechanism. It significantly increased MDA level but no con-
siderable changes in thiol level and also catalase activity in
liver tissue (Khazdair etal. 2016). An additional study also
used curucumin with same dosing alone or in combination
with Nigella sativa (200mg/kg) beside the same dose of
DOX, and they found that thiol level and also CAT activity
increased in treatment groups (Mohebbati etal. 2017). In
another study, DOX was administrated for 15days (1mg/
mL/kg/day, i.p.), and nanocurcumin supplement was admin-
istrated for 14days (100mg/kg/day orally). However, it did
not show significant antioxidant and anti-apoptosis effect
(Sadat-Hoseini & DabidiRoshan 2017).
Virgin coconut oil andCurcuma longa
The pure coconut oil like virgin coconut oil (VCO) is a strong
antioxidant and has several beneficial characteristics which
make it effective against the liver injury caused by chemo-
therapeutic agents (Famurewa etal. 2017). Recently, Yenni
etal. conducted a study comparing the hepatoprotective

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activity of VCO and Curcuma longa by evaluating the AST
and ALT level in Wistar rats. They named the treatments as
group I (DOX 5mg/kg + 6ml VCO), group II (DOX 5mg/
kg + Curcuma longa 100mg/kg), and group III (DOX 5mg/
kg + 6ml VCO + Curcuma longa 100mg/kg). Their results
demonstrated that DOX greatly increased the AST and ALT
and caused significant liver injuries, but treatment with a
combination of the VCO and Curcuma longa resulted in
significant hepatoprotective effects (Yenny etal. 2020). The
probable mechanism of its action is related to its antioxidant
properties but is not assessed in this study.
Ganoderma applanatum extract
In 2014, Lalmuansangi etal. explored the ability of the medic-
inal fungus Ganoderma applanatum (GAP) in providing
protective effects against DOX-induced toxicity in Dalton’s
lymphoma ascites (DLA)-bearing mice. Their study demon-
strated that treatment of DLA mice with DOX (20mg/kg i.p.
on day 1 + 0.5ml/day vehicle p.o.) significantly increased the
serum levels of AST, ALT, and LDH. However, co-treatment
of DOX with intraperitoneal injection and G. applanatum
(0.5ml NS i.p. on day 1 + 0.5ml/day 1% ethanol p.o.) resulted
in diminished levels of GSH and decreased activities of glu-
tathione-s-transferase, catalase, and superoxide dismutase,
and antioxidant property is its main proposed mechanism of
action. Their results also revealed that among various sol-
vent extracts of G. applanatum, methanolic extract showed
the highest phenolic and flavonoid contents compared to the
aqueous and chloroform extracts (Lalmuansangi etal. 2020).
Berberine
Berberine is an isoquinoline alkaloid, which is extracted
from the traditional Chinese plant Coptis chinensis and is
used for treatment of various infectious diseases. However,
recent studies have established that this alkaloid has a wide
range of pharmacological activities, including antidiabetic,
anti-inflammatory, and antitumor effects (Wang etal. 2020).
In particular, both animal and clinical investigations have
reported that berberine is beneficial in protection against
ROS formation (Cho etal. 2005). In a study, Zhao etal.
observed an increased mortality rate, a declined body
weight, and increased plasma ALT and AST level in DOX-
treated mice (2.5mg/kg i.p.). These changes were largely
prevented by pretreatment with berberine (60mg/kg i.p.)
(Zhao etal. 2012). Its mechanism of action did not define in
this study and should be determined in the future.
Silymarin andchlorogenic acid
Silymarin is an extract of Silybum marianum, which is
famous historically for its hepatoprotective properties
via apoptotic and antioxidant mechanisms (Gillessen &
Schmidt. 2020). Patel etal. evaluated the effects of sily-
marin pretreatments at the dose of 16mg/kg/day p.o. on
DOX-induced liver injuries in male ICR rats. The results
demonstrated an increased body weight in DOX + silymarin.
In addition, it diminished undesirable histopathological and
functional changes and mortality rate and prevented DOX-
induced oxidative stress (marked by decreasing malondial-
dehyde). Significant amelioration of DOX-induced Bcl-xL
decrease and PARP increase was also observed in this group
(Patel etal. 2010).
In the second study, Rašković etal. used a higher dose
of silymarin (60mg/kg/day p.o) for a time span of 12days
beside DOX (1.66mg/kg i.p. QOD) in male Wistar rats.
Their study showed a significant change in body weight,
ECG, oxidative stress parameters, serum ALT, AST, LDH,
and creatine kinase levels and histopathological preparations
of heart and liver specimens. They concluded that silymarin,
at the examined dose, had a protective influence on the liver
(and heart) tissues against DOX-induced toxicity (Rašković
etal. 2011).
The third study, conducted by Abbas etal. evaluated the
protective effects of silymarin in combination with chloro-
genic acid (CGA) 1.5mg/kg, on DOX-induced hepatotox-
icity (206.7mg/kg) every other day for 4weeks in Albino
rats. The results demonstrated that CGA caused a significant
decrease in apoptosis in hepatic cells (marked by caspase-3
and nuclear factor-κB levels), significant amelioration of
hepatic oxidant status (marked by decreasing malondialde-
hyde and superoxide dismutase), and significant decrease in
hepatic inflammatory markers (TNF-α and IL1β) compared
with DOX treatment alone (Abbas etal. 2020).
It should be mentioned that the administered dose of sily-
marin in abovementioned studies varied too much, and daily
dose of 16- 103mg/kg was administered in these three stud-
ies. The proposed mechanisms of action were anti-inflam-
matory, antioxidant, and anti-apoptotic ones.
Following these three animal studies, three clinical trials
were also performed on silymarin. In first study, Mshemish
etal. patients were randomly assigned to one of three groups
of fluorouracil/doxorubicin/cyclophosphamide (FAC) alone
(n = 24), FAC plus low-dose silymarin (210mg per day,
n = 25), and FAC plus high-dose silymarin (420mg per day,
n = 25), for three courses of 21days. Silymarin showed a
dose and time-dependent prophylactic effect at the end of
the first, second and third chemotherapy courses. But no sig-
nificant change in total bilirubin serum level was found after
treatment with silymarin (Mshemish etal. 2011). However,
they only assessed liver function tests with no ultrasonogra-
phy or transient elastography (TE) assessment, and silymarin
was used as a preventive measure.
In the second randomized clinical trial (RCT), 99 patients
with invasive breast carcinoma receiving chemotherapy that

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contained Adriamycin or epirubicin, cyclophosphamide,
docetaxel, or paclitaxel randomly received silymarin 70mg
PO three times daily or the placebo during their treatment
course. The patients had mild rises in AST, ALT, and biliru-
bin in both groups, but the changes were less notable in the
study group, with significant difference between two groups
(Mohaghegh etal. 2015).
In third study, Askarpour Moezian etal. assessed the
therapeutic effect of silymarin, 140mg three times a day on
DOX-induced hepatotoxicity in patients with non-metastatic
breast cancer who received doxorubicin/cyclophosphamide-
paclitaxel (AC-T) regimen; in contrast to the previous stud-
ies which focused on preventive effects, they found a non-
significant trend toward more severe hepatic injury in the
placebo based on ultrasonography. Besides, in silymarin
group, hepatic involvement grade based on ultrasonogra-
phy considerably reduced after intervention. However, no
difference was found between two groups based on TE and
liver function tests (Askarpour etal. 2021). These three stud-
ies are summarized in Table2. As TE has been repeatedly
validated and has shown overall good accuracy in evaluat-
ing fibrosis and cirrhosis in different settings, the promising
effect of silymarin based on ultrasonography should be con-
firmed in future well-designed RCT using TE as a measur-
ing tool. Moreover, the mechanism of action is better to be
assessed in human studies.
Boswellic acid
Acetyl 11-keto-b-boswellic acid (AKBA) is a pentacyclic
triterpenoid compound, which is known as the most effective
component of Boswellia serrata resin (Safayhi etal. 1992).
The antioxidant protective effect of AKBA is thought to
be mediated through activating the NF-E2-related factor 2
(Nrf2) pathways (Zhang etal. 2016). In the study of Barakat
etal., the Swiss albino rats received DOX (6mg/kg/w), with
or without protective doses of BOS (125, 250, and 500mg/
kg/day). The results demonstrated that treatment with BOS
significantly reduced ALT, AST, and malondialdehyde.
These findings were coupled with significant improvement
in histological features of the liver. BOS increased the Nrf2
and heme oxygenase-1 (HO-1) expression, which further
confirmed a possible mechanism for protective effects of this
agent, which is antioxidant property (Barakat etal. 2018).
Dioscin
Dioscin is a naturally derived triterpenoid saponin which has
protective activities against organ damage and acts vigorously
against metabolic diseases. Recent studies have shown the
therapeutic effects of dioscin on acute liver injury through
diminishing oxidative stress and inhibition of inflammation
through suppression of various pathways including NF-κB
(Liu etal. 2015). Based on these considerations, Song etal.
investigated the protective effects of dioscin on DOX-induced
liver injury by invitro (in AML-12 cells) and invivo (in male
mice) studies. For the invitro study, they used dioscin for 6, 12,
and 24h before DOX treatment (5mg/ml for 24h). For invivo
study, they used 15, 30, and 60mg/kg of dioscin. Their results
showed that dioscin significantly decreased DOX-induced
cell injury and ROS level and suppressed DOX-induced cell
apoptosis in AML-12 cells. Regarding the results from invivo
investigations, dioscin evidently decreased the levels of ALT,
AST, and malondialdehyde and increased the levels of super-
oxide dismutase, glutathione, and glutathione peroxidase. In
pursuit of the mechanism of this liver protection, they found
that dioscin significantly up-regulated the expression of silent
information regulator 1 (Sirt1) and HO-1 through increase of
Nrf2 and inhibited the expression of forkhead box protein O1
(FOXO1) and kelch-like ECH-associated protein-1 (Keap1),
resulting in the inhibition of oxidative stress. Dioscin also obvi-
ously decreased the NF-κB protein level and the mRNA levels
of TNF-α, IL-1β, and IL-6, which resulted in suppression of
inflammation. On the other hand, dioscin inhibited apoptosis
through regulation of p53 and BCL-2. These results demon-
strated that dioscin inhibited DOX-induced hepatotoxicity via
Sirt1/FOXO1/NF-κB signal (Song etal. 2019). So, all three
anti-apoptotic, anti-inflammatory, and antioxidant mechanisms
could be considered for its action.
Edible brown alga Ecklonia stolonifera
Species of Ecklonia have been reported to be potent phlo-
rotannin-rich raw materials. Phlorotannins are secondary
metabolites of phloroglucinol which have been polymer-
ized through different solvents including ether, phenyl, or
1,4-dibenzodioxin. These polyphenolic compounds show a
variety of bioactivities, including anti-diabetic, anti-inflam-
matory, and hepatoprotective activities (Kim etal. 2005).
Jung etal. investigated the protective capacity of 14 edible
varieties of Korean seaweed against DOX-induced liver
injury invitro in primary rat hepatocytes (Jung etal. 2014).
This study was carried out by adding 10µl of 5-µM DOX to
each well and 2days incubation and half maximal effective
concentration (EC50) values of 2.0, 2.5, 3.0, and 15.0µg/
ml, respectively. The results demonstrated significant pro-
tective effects of EtOAc and n-BuOH fractions of ethanol
extract of Ecklonia stolonifera with EC50 values of 3.0µg/
ml and 8.4µg/ml, respectively, as compared with positive
control silymarin (EC50 value = 8.0µg/ml). In addition, they
observed concurrent cytotoxic effects at hepatoprotective
concentration observed with CH2Cl2 fraction. However, no
significant protective effect was observed in N-hexane and
H2O fractions (Jung etal. 2014). Its mechanism of action
is not well defined.

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Chrysin
Chrysin (5,7-dihydroxyflavone) is a natural flavonoid which
has been isolated from different plants, as well as honey and
propolis. This flavonoid has important pharmacological prop-
erties, including antidiabetic, antioxidant, and anti-inflamma-
tory effects and can prevent chemoresistance through inhibi-
tion of efflux proteins (Pushpavalli etal. 2010). Rashid etal.
evaluated the protective efficacy of chrysin (CH) (40 and
80mg/kg PO) against DOX-induced oxidative stress and kid-
ney and liver injuries (40mg/kg) in male Wistar rats. Treat-
ment with CH significantly diminished serum levels of ALT,
AST, and LDH. These observations were also confirmed by
the histopathological findings and antioxidant enzyme level
changes, which were highly reversed by chrysin via antioxi-
dant mechanism (Rashid etal. 2013).
Naringin andnaringenin
Naringin (NIN) is a flavonoid extracted from grapefruit or
other citrus fruits. This flavonoid is stated to have a variety of
pharmacological characteristics, including antioxidant, antia-
therogenic, and anti-inflammatory activities (Nie etal. 2012).
In 2017, Liu etal. investigated the role of NIN in DOX-induced
toxicity invitro and invivo. For invitro study, they used Hela
cells seeded onto a 96-well plate and then added 20µl of DOX
(1.6 to 10.0µg/mL) and NIN (200 to 2000µmol/L) at different
concentrations. For invivo purpose, they used 32 Hela cells-
bearing athymic nude mice in 4 groups: control; DOX (5mg/
kg); NIN (20mg/kg) and DOX + NIN. DOX and NIN were
administrated with 3-day interval for 5 times. A significant
antitumor efficacy was observed in DOX + NIN group in both
invitro and invivo studies, in addition to significant inhibition
of DOX-induced weight loss and other systemic sides effects
and diminishing hepatocyte necrosis (Liu etal. 2017).
Naringenin (NIGN) has long been considered as an
important ingredient of traditional Chinese medicine. It has
been reported that this flavonoid has exceptional biological
properties ranging from antioxidant to anticancer (Rehman
etal. 2018). Wali etal. investigated the role of naringenin
(50 and 100mg/kg/day p.o. 20 d) on DOX-induced hepato-
toxicity (20mg/kg i.p. on 20th day) after 20days of concomi-
tant use. Naringenin diminished ROS production and ROS-
induced lipid peroxidation and replenished the suppressed
antioxidant armory, marked by catalase, glutathione reduc-
tase, superoxide dismutase, glutathione, and glutathione
peroxidase. Furthermore, naringenin significantly dimin-
ished DOX-induced hepatotoxicity biochemichal (ALT,
AST, ALP, LDH) as well as inflammatory markers (NF-kB,
TNF-α, IL-1β, PGE-2, TGF-β, and IL-6) (Wali etal. 2020).
Its antioxidant and anti-inflammatory effects for prevention
of liver injury should be addressed in future studies, using
lower doses of DOX.
DL‑alpha lipoic acid
Lipoic acid is a naturally-occurring compound which has a
great potential against oxidative metabolism and participates
as protein bound lipoamide in alpha-keto acid dehydrogenase
complexes in mitochondria. It can be converted to a more
active antioxidant molecule, dihydroplipoic acid (Rochette
etal. 2013). In a study by Anandakumar etal., protective
efficacy of DL-alpha lipoic acid (75mg/kg LA single injec-
tion i.p., 24h before DOX) on DOX-induced hepatotoxicity
(15mg/kg i.p.) was investigated in Wistar rats. The adminis-
tration of DOX resulted in an elevation in ALT, AST, ALP,
and LDH level and malondialdehyde, which may be amelio-
rated by DL-alpha lipolic acid (Anandakumar etal. 2007).
Grape seed andskin extract
Grape seed and skin extract (GSSE) is a mixture of various
polyphenolic compounds which is considered to be protec-
tive against DOX-induced cardiotoxicity. The cardioprotective
effects of GSSE have been closely attributed to its iron chelat-
ing property (Quiles etal. 2002). However, there is paucity of
studies regarding its hepatoprotective effects against DOX. In
the study of Monki etal., Wistar rats were treated with GSSE
(500mg/kg/day) for 8days. At the 4th day of treatment, they
received DOX (20mg/kg), and at the 9th day, the rat’s liv-
ers were collected and assessed for oxidative stress status.
According to the results, treatment with DOX alone resulted
in more than 900% increase in MDA and significant increases
in peroxidase and superoxide dismutase activities. However,
GSSE significantly decreased DOX-induced elevation of
serum enzymes (ALT, AST, and bilirubin) and stimulated
lipid peroxidation and the levels of antioxidant markers (GSH,
CAT, SOD, GPx, GR, GST, and G6PD) (Mokni etal. 2015).
Artemisinin
Artemisinin (ATS) is a sesquiterpene lactone which is iso-
lated from Artemisia annua and is known as an antimalarial
agent. However, studies have also demonstrated that this
compound is an effective anti-inflammatory, anti-oxidative,
and anti-cancer agent. Recently, Aktaş etal. evaluated the
efficacy of ATS (7mg/kg/day (ATS7) and 35mg/kg/day
(ATS35) for 14days) on DOX-induced liver damage (10mg/
kg, single dose). DOX, when used alone, resulted in sig-
nificant degeneration of liver and increasing histological
involvement scores and Caspase-3 and TNF-α expression
in hepatocytes. However, treatment with DOX + ATS7 and
DOX + ATS35 led to decrease in the expression of iNOS,
apoptotic markers and NF-kB and diminishment in the liver
damages caused by DOX (Aktaş etal. 2020). So, antioxidant
and anti-apoptotic and anti-inflammatory potentials are key
proposed mechanisms of action.

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Morin
Morin is a flavonoid which is presented in members of the
Moraceae family, and white berry and cranberry branches
are rich in this compound. It inhibits the production of ROS
in high-level glucose-treated rats and inhibits apoptosis
through stimulation of Bcl-2 and antioxidant genes expres-
sion (Kapoor & Kakkar 2012). Recently, Kuzu etal. inves-
tigated the protective effects of Morin (100mg/kg, on the
8th day) against DOX-induced hepatotoxicity (40mg/kg, 10
d) in Wistar albino rats. Adminstration of morin along with
DOX decreased MDA levels in a dose-dependent manner
and significantly increased antioxidant markers (SOD, CAT,
and GPx). Furthermore, this combination had regulatory
effect on TNF-α, IL-1β, and NF-κB levels. DOX + Morin
treatment also significantly increased the expression of
anti-apoptotic marker Bcl-2 and decreased Bax levels dose-
dependently and resulted in significant preservation of liver
structure against DOX damages. So, all three antioxidant,
anti-apoptosis, and anti-inflammatory mechanisms could be
involved in its preventive effects (Kuzu etal. 2019).
Astaxanthin
Astaxanthin (ATX) is a carotenoid which is derived from
Haematococcus pluvialis and has strong antioxidant activi-
ties. ATX structurally can act as a free radical scavenger by
attracting free radicals to its unpaired electrons (Visioli &
Artaria 2017). Ma etal. assessed the hepatoprotective effects
of ATX (50 and 100mg/kg/day, administrated for 3weeks)
against DOX (6mg/kg single i.p.). A significant increase
in body weight and food intake in ATX groups was found
in comparison with the DOX group. Significant preserva-
tion of hepatocytes against DOX-induced injuries was also
observed in ATX group. In addition, significant increase
in anti-apoptotic and antioxidant markers (SOD, CAT and
GPx) was observed in ATX groups (Ma etal. 2020).
Asiatic acid
Asiatic acid (AA) is the effective constituent of Centella
asiatica, which is known because of its anti-cancer, anti-
diabetic, and anti-inflammatory properties (Matsuda etal.
2001). Kamble etal. evaluated the ameliorative effects of
AA (5, 10, and 20mg/kg/day PO, 7d) on DOX-induced car-
diac and hepato-renal toxicities (65.75mg/kg IV, 2d before
the end of the study) with Nrf2 transcriptional factor acti-
vation in Wistar rats. According to their report, significant
DOX-induced upsurge of injury marker enzymes (LDH,
ALT and AST) was observed. However, significant increase
in antioxidant markers (SOD and GSH) was observed in
AA20 group, and it decreased DOX-induced elevation of
LPO and protected liver architecture (Kamble & Patil 2018).
Zataria multiflora andcarvacrol
Zataria multiflora (ZM), which is also known as Avishan
Shirazi, is a member of Lamiaceae family. This plant has dif-
ferent effective ingredients, such as p-cymene (10%), thymol
(16%), and carvacrol (CAR) (52%) (Kavoosi etal. 2012).
ZM is proposed to be effective against various conditions,
including asthma and cancer, and has different pharmaco-
logical potentials such as anti-inflammatory and antioxidant
effects (Silva etal. 2012). Given these properties, Mohebbati
etal. investigated the effects of ZM (200mg/kg/d IV) and
CAR (20mg/kg/d IV) against hepatic injuries caused by
DOX (5mg/kg IV) in Wistar rats for 28days. A significant
increase in body weight of the rats in DOX + CAR group
was found compared to the DOX group. In addition, a sig-
nificant reduction in serum ALP, AST, and ALT levels was
observed in DOX + CAR group. The catalase activity was
increased in both DOX + CAR and DOX + ZM groups, but
no significant differences in SOD activities were observed
among all groups (Mohebbati etal. 2018). It seems that car-
vacrol is the main active compound of ZM for prevention
of DOX induced hepatotoxicity via antioxidant mechanism.
Acacia hydaspica ethyl acetate fraction
Acacia hydaspica R. Parker (AHE) is a member of Legumi-
nosae family, which has important pharmacological activities.
Its bark and seeds are rich in tannins, have strong antioxidant,
anti-inflammatory, and anti-cancer properties, and protect
against cisplatin-induced DNA damage (Afsar etal. 2017).
Afshar etal. evaluated the effect of AHE extract (200 and
400mg/kg/day, 6weeks) on lipid peroxidation, antioxidant
status, and liver function and integrity in doxorubicin (3mg/
kg/week) treated SD rats. Their results demonstrated signifi-
cant amelioration of DOX-induced body weight loss and an
increase in liver weight with AHE in a dose dependent man-
ner. Significant diminishment in ALT, AST, ALP, LDH, and
total and direct BL with AHE was also observed dose depend-
ently. The lipid profile, including total cholesterol, triglyceride
(TG), and low density lipoprotein (LDL)-c decreased with
AHE treatments in both concentrations of AHE, but increase
in HDL was only observed in AHE 400 group. Antioxidant
parameters (POD, SOD, CAT, QR, GSH, GR, GST, GGT, and
GPx) were also decreased with AHE treatments dose depend-
ently. AHE at both doses also significantly decreased liver
injuries, determined by histopathological parameters (Afsar
etal. 2019). So, antioxidant action may be the main mecha-
nism of this herbal compound hepato-protection.
p‑Coumaric acid
p-Coumaric acid (pCA) is a hydroxy derivative of cinnamic
acid, which is presented in a variety of edible plants such

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1 3
as barley grains, peanuts, tomatoes, and garlic. This com-
pound is an antioxidant with anti-inflammatory and antitu-
mor effects and is efficacious against cardiovascular disease
(Walker etal. 2011). Recently, Rafiee etal. assessed the
effects of pCA (100mg/kg/day, 5days) on adriamycin-
induced hepatotoxicity (15mg/kg on the 5th day) in Wistar
rats. pCA pretreatment resulted in significant decrease in
serum ALT, AST, ALP, TG, total cholesterol, LDL-c, and
total BL and an increase in HDL and serum ALB. In addi-
tion, pCA decreased lipid peroxidation (marked by MDA)
and significantly increased antioxidant enzymes activities
(GPx, SOD, and CAT), while prevented DOX-induced liver
histopathological changes (Rafiee etal. 2021). So, antioxi-
dant action may be the main mechanism of this herbal com-
pound hepato-protection.
Ziziphus jujuba Mill
Ziziphus jujuba Mill (ZJ) has been long traditionally used
for biliousness, obesity, cough, headache, and some other
indications. In the last two decades, ZJ has been considered
as a potential treatment of cancer, leukorrhea, tuberculosis,
and cardiovascular disorders (Chen etal. 2017). Also, ZJ can
play an antibacterial, hypotensive, and anti-inflammatory
role. Khajavi Rad etal. investigated the function of a stand-
ardized extract of ZJ against adriamycin-induced liver, heart,
and brain toxicity (20mg/kg PO, thrice daily) in Wistar rats.
Administration of ZJ significantly decreased the biochemical
enzymes (AST, ALT, LDH) and total and direct bilirubin.
Oxidative condition of ZJ treated rats improved considerably
compared to the DOX group (Khajavi Rad 2021).
Thyme oil andthymol
Thymol is a monoterpene phenol which is found in some
plants such as Thymus vulgaris, and it has been reported to
exhibit antioxidant, anti-bacterial, anti-inflammatory, and
anti-apoptosis properties (Tsai etal. 2011, El-Sayed etal.
2015). In recent years, Ahmed etal. study on Wistar rats
demonstrated that the combination of thyme oil (250mg/
kg) or thymol (100mg/kg) every other day for 5weeks
with 2mg/kg DOX once a week for 2weeks could improve
liver structure and integrity, hepatic necrosis, apoptosis,
and fibrosis in treated rats. Moreover, thyme oil and thymol
were effective in reversal of DOX-induced rise in serum
ALT, AST, ALP, total BL, and serum albumin levels. Also,
they observed an increase in serum level of AFP (CA 19.9),
TNFα, and IL-4 in DOX-treated rats which was returned to
normal values in rats treated with thyme oil and thymol. An
assay on oxidant and antioxidant factors revealed that thyme
oil and thymol can ameliorate DOX-induced increase of
LPO and decrease content of GSH and activities of GST and
GPx. Besides, they inhibited apoptosis through increasing
Bcl-2 mRNA expression and decreasing p53 expression
(Ahmed etal. 2022). So, it may show preventive effects via
antioxidant and anti-apoptosis properties.
Mangiferins
Mangiferin is a bioactive extract of an Indonesian mango,
called Mangifera foetida (Shah etal. 2010). This compound
possesses antioxidant and free radical scavenging properties
(Pardo-Andereu etal. 2006). Based on these considerations,
Husna etal. investigated the protective effect of mangiferin
(50 and 100mg/kg PO, 5weeks) on liver damage of DOX
(2.5mg/kg every 2days for 2weeks) in SD rats. Their result
demonstrated that the treatment with mangiferin resulted in
significant reduction of ALT and AST serum levels. Besides,
mangiferin declined lipid peroxidation (marked by MDA
level) and increased content of GSH and SOD activity. So,
it has antioxidant property for preventing hepatotoxicity
(Husna etal. 2022).
Conclusion
The aim of the current study was to appraise the ameliorative
effects of various herbal compounds on the hepatotoxicity
of DOX. Anthracyclines, including doxurobicin, have been
routinely used in treatment of various cancers. However, the
clinical use of these medications is limited because of severe
toxic effects on the various body tissues, including heart,
liver, kidneys, and nervous system particularly in high cumu-
lative dose. The exact mechanism of these severe toxicities of
DOX is not completely understood, but ROS is thought to be
a key factor, interfering in the mitochondrial electron trans-
port chain (ETC) and apoptosis. Besides, abundant evidence
is suggesting the role of inflammation in DOX-induced organ
damage. Considering the abovementioned probable mecha-
nisms of DOX toxicity various invitro and invivo studies
focused on compounds with antioxidant, anti-inflammatory,
and anti-apoptotic properties for prevention of this complica-
tion. In this review, 40 related studies are included, 35 studies
were invivo, two studies were invitro researches (2 stud-
ies both invivo and invitro), and three others were clinical
trials. Most of the studies focused on biochemical (n = 26)
and histopathological (n = 30) aspects of hepatotoxicity and
showed that the assessed compounds considerably improved
these aspects in DOX treated animals.
It is important to mentioned that these compounds mostly
have demonstrated promising efficacy on liver injury his-
topathology (necrosis, fibrosis…) and biochemical factors
(AST, ALT, ALP, LDH…) and reducing oxidative stress
markers (MDA, ROS, CAT, SOD, GSH…), inflammatory
cytokines (IL6, IL-1B, TNFα, …), and apoptotic factors
(caspase3, Bax, Bcl2…) in cellular and animal studies.

Naunyn-Schmiedeberg's Archives of Pharmacology
1 3
Actually, the most common proposed mechanism of
action for these compounds in reviewed articles was anti-
oxidant effect which was defined in 30 studies. Anti-
inflammatory and anti-apoptotic mechanisms were in
second and third place, proposed in 14 and 10 studies,
respectively, and anti-angiogenic effect was also sug-
gested in one study. Moreover, in 12 studies, significant
increment of animals’ body weight was noteworthy,
and in 4 studies, reduction of mortality was a promis-
ing finding. Antioxidant effect was the common mecha-
nisms defined for all these four compounds; however, the
mechanism should be confirmed in human studies which
is lacking. Further human studies particularly on these
compounds including berberine, silymarin, dioscin and
gingerol could be logical. Only three available clinical
trials assessed silymarin hepatoprotective effect. Two
studies showed its significant preventive effect, and
the other one focused on its therapeutic effect on DOX-
induced liver injury, which was just confirmed based
on ultrasound assessment but not TE or liver enzyme
changes. It is also noticeable that naringin and narin-
genin, beside hepatoprotective effect, showed some anti-
tumor abilities which may be an interesting finding if it
could be proven in future well-designed human studies.
It is noteworthy that some other compounds which are
considered in this review like silymarin and curcumin
also showed promising anti-tumor effects in previous
researches, and considering this evidence beside their
hepatoprotective effects makes them good targets for
future studies in various cancers.
It also should be mentioned that in lots of reviewed
invivo studies (QE, GAP, CH, NIGN, GSSE, morin, AA,
and NM), doxorubicin is administered in considerably
higher than therapeutic dose (if converted to human equiva-
lent dose), and it was much more than LD50 of DOX which
is about 12–15mg/kg for mice (Aston etal. 2017). So, the
reported hepatoprotective efficacy did not make sense in
practice before being confirmed in future studies on DOX
with therapeutic doses.
In conclusion, the promising findings of preclinical
studies should be confirmed in well-designed clinical
trials for better judgment. Actually, invivo studies are
performed under controlled condition on healthy animals.
So, their findings could not be generalized to humans.
Besides, pharmacodynamic and pharmacokinetic interac-
tions between these compounds and chemotherapy regi-
mens should be assessed in human studies. Definition of
the proper safe dose of these compounds for human use is
another challenge. Some of these compounds were previ-
ously used in human for other indications, and their safe
doses are determined; however, for some other agents, this
safe dose should be calculated based on animal adminis-
tered dose which may be difficult.
Author contribution Faezeh Mahmoudi searched the databases and
wrote the manuscript. Sepideh Elyasi defined the manuscript’s subject
and edited the manuscript. Omid Arasteh searched the databases and
edited the manuscript.
Availability of data and materials Not applicable.
Declarations
Ethics approval and consent to participate Not applicable.
Consent for publication All authors approved manuscript in present
format for publication.
Competing interests The authors declare no competing interests.
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