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

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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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Abbreviations

DOX:

Doxorubicin

ROS:

Reactive oxygen species

NADPH:

Nicotinamide adenine dinucleotide 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

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

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  1. Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, P.O. Box 91775-1365, Mashhad, Iran

    Faezeh Mahmoudi, Omid Arasteh & Sepideh Elyasi

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  1. Faezeh Mahmoudi
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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.

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Mahmoudi, F., Arasteh, O. & Elyasi, S. Preventive and therapeutic use of herbal compounds against doxorubicin induced hepatotoxicity: a comprehensive review. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1595–1617 (2023). https://doi.org/10.1007/s00210-023-02429-1

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