None Herbal Agents as Preventive and Therapeutic Measures for Doxorubicin Induced Hepatotoxicity: A Comprehensive Review
Abstract
Cancer is one of the most common human diseases and a leading cause of human mortality in rencent years. Doxorubicin (DOX) is an important anti-cancer agent belonging to anthracyclines drug category. This chemotherapeutic agent acts against cancer cells through different mechanisms; however, its use is related with numerous acute and chronic dose-related side effects and toxicities including hepatotoxicity. The aim of this study was to conduct a comprehensive review of in vitro, in vivo and any human studies regarding the protective effects of synthetic 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” to find experimental and preclinical studies regarding the effects of various compounds on DOX-induced hepatotoxicity. Twenty-one eligible studies to the end of May 2022 finally were reviewed (19 in vivo and 2 both in vivo and in vitro studies). Our results demonstrated that all of these drugs, except acetylsalicylic acid, had considerable hepatoprotective effects against DOX (deferoxamine had a mild effect). In addition, except glutathione, none of the studied drugs and compounds attenuated the antitumor efficacy of DOX treatment. Moreover, no human study was available in this fieild. Altogether, our results demonstrated that most of compounds with anti-apoptosis, anti-inflammatory and antioxidant properties are efficacious against DOX-induced hepatotoxicity and may have potential for being considered for inclusion in the chemotherapeutic regimes of cancer patients, after fully been assessed in well-desgined large clinical trials.
1.Ferlay J, Colombet M, Soerjomataram I, et al. Cancer statistics for the year 2020: An overview. Int J Cancer. 2021;149(4):778-89.
2.Sak K. Chemotherapy and dietary phytochemical agents. Chemother Res Pract. 2012;2012:282570-.
3.Thorn CF, Oshiro C, Marsh S, et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics. 2011;21(7):440-6.
4.Kalyanaraman B. Teaching the basics of the mechanism of doxorubicin-induced cardiotoxicity: Have we been barking up the wrong tree? Redox Biology. 2020;29:101394.
5.Shivakumar P, Rani MU, Reddy AG, Anjaneyulu Y. A study on the toxic effects of Doxorubicin on the histology of certain organs. Toxicol Int. 2012;19(3):241-4.
6.Dos Santos Arruda F, Tomé FD, et al. Doxorubicin-induced cardiotoxicity and cardioprotective agents: classic and new players in the game. Curr Pharm Des. 2019;25(2):109-18.
7.Twelves CJ, Dobbs NA, Gillies HC, James CA, Rubens RD, Harper PG. Doxorubicin pharmacokinetics: the effect of abnormal liver biochemistry tests. Cancer Chemother Pharmacol. 1998;42(3):229-34.
8.Sahlan M, Rizka Alia Hapsari N, Diah Pratami K, et al. Potential hepatoprotective effects of flavonoids contained in propolis from South Sulawesi against chemotherapy agents. Saudi J Biol Sci. 2021;28(10):5461-5468.
9.Superfin D, Iannucci AA, Davies AM. Commentary: Oncologic drugs in patients with organ dysfunction: a summary. Oncologist. 2007;12(9):1070.
10.Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.
11. Ateyya H, Yosef H, Nader MA. Ameliorative effect of trimetazidine on cisplatin-induced hepatotoxicity in rats. Can J Physiol Pharmacol. 2016;94(2):225-30.
12.Salouege I, Ben Ali R, Ben Saïd D, et al. Means of evaluation and protection from doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. J Cancer Res Ther. 2014;10(2):274-8.
13.Sikandar A, Farhat K, Afzal A, Ajmal K, Laeeq M, Khokhar A. Protective effects of trimetazidine against doxorubicin-induced cardiotoxicity and hepatotoxicity in mice. J Ayub Med Coll Abbottabad. 2020;32(3):304-9.
14.Mansouri E, Jangaran A, Ashtari A. Protective effect of pravastatin on doxorubicin-induced hepatotoxicity. Bratisl Lek Listy. 2017;118(5):273-7.
15.Alkhatib MH, Alkreathy HM, Omar MIA, Balamash KS, FaizaAbdu, Esmat A. Doxorubicin supplemented with pravastatin in lipid nanoemulsion induces antineoplastic activity with limited hepatotoxicity and cardiotoxicity in tumor-bearing mice. Asian Journal of Pharmaceutical Research and Health Care. 2021;13:17-29.
16.Akindele AJ, Oludadepo GO, Amagon KI. Protective effect of carvedilol alone and coadministered with diltiazem and prednisolone on doxorubicin and 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats. Pharmacol Res Perspect. 2018;6(1):e00381.
17.Bartosz M, Kedziora J, Bartosz G. Antioxidant and prooxidant properties of captopril and enalapril. Free Radic Biol Med. 1997;23(5):729-35.
18.Abd El-Aziz MA, Othman AI, Amer M, El-Missiry MA. Potential protective role of angiotensin-converting enzyme inhibitors captopril and enalapril against adriamycin-induced acute cardiac and hepatic toxicity in rats. J Appl Toxicol. 2001;21(6):469-73.
19.Inglesi M, Nicola M, Fregnan GB, Bradamante S, Pagani G. Synthesis and free radical scavenging properties of the enantiomers of erdosteine. Farmaco (Societa chimica italiana : 1989). 1994;40(11):703-8.
20.Yagmurca M, Bas O, Mollaoglu H, et al. Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats. Arch Med Res. 2007;38(4):380-5.
21.Link G, Tirosh R, Pinson A, Hershko C. Role of iron in the potentiation of anthracycline cardiotoxicity: identification of heart cell mitochondria as a major site of iron-anthracycline interaction. J Lab Clin Med. 1996;127(3):272-8.
22.Saad SY, Najjar TA, Al-Rikabi AC. The preventive role of deferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats. Pharmacol Res. 2001;43(3):211-8.
23.Bulucu F, Ocal R, Karadurmus N, et al. Effects of N-acetylcysteine, deferoxamine and selenium on doxorubicin-induced hepatotoxicity. Biol Trace Elem Res. 2009;132(1-3):184-96.
24.Cengiz O, Baran M, Balcioglu E, et al. Use of selenium to ameliorate doxorubicin induced hepatotoxicity by targeting pro-inflammatory cytokines. Biotech Histochem. 2021;96(1):67-75.
25.Mirkov SM, Djordjevic AN, Andric NL, et al. Nitric oxide-scavenging activity of polyhydroxylated fullerenol, C60(OH)24. Nitric Oxide. 2004;11(2):201-7.
26.Grebowski J, Kazmierska P, Krokosz A. Fullerenols as a new therapeutic approach in nanomedicine. Biomed Res Int. 2013;2013:751913.
27.Jacevic V, Djordjevic A, Srdjenovic B, et al. Fullerenol nanoparticles prevents doxorubicin-induced acute hepatotoxicity in rats. Exp Mol Pathol. 2017;102(2):360-9.
28.Petrovic D, Seke M, Borovic ML, et al. Hepatoprotective effect of fullerenol/doxorubicin nanocomposite in acute treatment of healthy rats. Exp Mol Pathol. 2018;104(3):199-211.
29.Lawler JM, Barnes WS, Wu G, Song W, Demaree S. Direct antioxidant properties of creatine. Biochem Biophys Res Commun. 2002;290(1):47-52.
30.Bredahl EC, Hydock DS. Creatine supplementation and doxorubicin-induced skeletal muscle dysfunction: an ex vivo investigation. Nutr Cancer. 2017;69(4):607-15.
31.Aljobaily N, Viereckl MJ, Hydock DS, et al. Creatine Alleviates doxorubicin-induced liver damage by inhibiting liver fibrosis, inflammation, oxidative stress, and cellular senescence. Nutrients. 2020;13(1):41.
32.Villani F, Galimberti M, Monti E, et al. Effect of glutathione and N-acetylcysteine on in vitro and in vivo cardiac toxicity of doxorubicin. ree Radic Res Commun.1990;11(1-3):145-51.
33.Shen By, Chen C, Xu Yf, et al. Is the combinational administration of doxorubicin and glutathione a reasonable proposal? Acta Pharmacol Sin. 2019;40(5):699-709.
34.Daga M, de Graaf IAM, Argenziano M, et al. Glutathione-responsive cyclodextrin-nanosponges as drug delivery systems for doxorubicin: Evaluation of toxicity and transport mechanisms in the liver. Toxicol In Vitro. 2020;65:104800.
35.Rochette L, Ghibu S, Richard C, Zeller M, Cottin Y, Vergely C. Direct and indirect antioxidant properties of α-lipoic acid and therapeutic potential. Mol Nutr Food Res. 2013;57(1):114-25.
36.Anandakumar PP, Malarkodi SP, Sivaprasad TR, Saravanan GD. Antioxidant DL-alpha lipoic acid as an attenuator of adriamycin induced hepatotoxicity in rat model. Indian J Exp Biol. 2007;45(12):1045-9.
37.Xie C, Li X, Wu J, Liang Z, et al. Anti-inflammatory Activity of Magnesium Isoglycyrrhizinate Through Inhibition of Phospholipase A2/Arachidonic Acid Pathway. Inflammation. 2015;38(4):1639-48.
38.Wu Z, Zhang Y, Song T, et al. Magnesium isoglycyrrhizinate ameliorates doxorubicin-induced acute cardiac and hepatic toxicity via anti-oxidant and anti-apoptotic mechanisms in mice. Exp Ther Med. 2018;15(1):1005-12.
39.Green D, Hirsh J, Heit J, Prins M, Davidson B, Lensing AW. Low molecular weight heparin: a critical analysis of clinical trials. Pharmacol Rev. 1994;46(1):89-109.
40.Deepa PR, Varalakshmi P. Protective effect of low molecular weight heparin on oxidative injury and cellular abnormalities in adriamycin-induced cardiac and hepatic toxicity. Chem Biol Interact. 2003;146(2):201-10.
41.Hinkley JM, Morton AB, Ichinoseki-Sekine N, Huertas AM, Smuder AJ. exercise training prevents doxorubicin-induced mitochondrial dysfunction of the liver. Med Sci Sports Exerc. 2019;51(6):1106-15.
42.Alishahi A, Roshan VD, Hedayyati M. Pretreatment effects of regular aerobic training on the IGF system and hepatotoxicity induced by doxorubicin in rats. Asian Pac J Cancer Prev. 2013;14(12):7427-31.
43.Ferroni P, Zanzotto FM, Scarpato N, et al. Risk Assessment for Venous Thromboembolism in Chemotherapy-Treated Ambulatory Cancer Patients. Med Decis Making. 2017;37(2):234-42.
44.Gökçe AB, Eren B, Sağır D, Demirel Yılmaz B. A histopathological and stereological study of the effects of acetylsalicylic acid on doxorubicin-induced hepatotoxicity in mice. Biotech Histochem. 2021;96(4):251-6.
2.Sak K. Chemotherapy and dietary phytochemical agents. Chemother Res Pract. 2012;2012:282570-.
3.Thorn CF, Oshiro C, Marsh S, et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics. 2011;21(7):440-6.
4.Kalyanaraman B. Teaching the basics of the mechanism of doxorubicin-induced cardiotoxicity: Have we been barking up the wrong tree? Redox Biology. 2020;29:101394.
5.Shivakumar P, Rani MU, Reddy AG, Anjaneyulu Y. A study on the toxic effects of Doxorubicin on the histology of certain organs. Toxicol Int. 2012;19(3):241-4.
6.Dos Santos Arruda F, Tomé FD, et al. Doxorubicin-induced cardiotoxicity and cardioprotective agents: classic and new players in the game. Curr Pharm Des. 2019;25(2):109-18.
7.Twelves CJ, Dobbs NA, Gillies HC, James CA, Rubens RD, Harper PG. Doxorubicin pharmacokinetics: the effect of abnormal liver biochemistry tests. Cancer Chemother Pharmacol. 1998;42(3):229-34.
8.Sahlan M, Rizka Alia Hapsari N, Diah Pratami K, et al. Potential hepatoprotective effects of flavonoids contained in propolis from South Sulawesi against chemotherapy agents. Saudi J Biol Sci. 2021;28(10):5461-5468.
9.Superfin D, Iannucci AA, Davies AM. Commentary: Oncologic drugs in patients with organ dysfunction: a summary. Oncologist. 2007;12(9):1070.
10.Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.
11. Ateyya H, Yosef H, Nader MA. Ameliorative effect of trimetazidine on cisplatin-induced hepatotoxicity in rats. Can J Physiol Pharmacol. 2016;94(2):225-30.
12.Salouege I, Ben Ali R, Ben Saïd D, et al. Means of evaluation and protection from doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. J Cancer Res Ther. 2014;10(2):274-8.
13.Sikandar A, Farhat K, Afzal A, Ajmal K, Laeeq M, Khokhar A. Protective effects of trimetazidine against doxorubicin-induced cardiotoxicity and hepatotoxicity in mice. J Ayub Med Coll Abbottabad. 2020;32(3):304-9.
14.Mansouri E, Jangaran A, Ashtari A. Protective effect of pravastatin on doxorubicin-induced hepatotoxicity. Bratisl Lek Listy. 2017;118(5):273-7.
15.Alkhatib MH, Alkreathy HM, Omar MIA, Balamash KS, FaizaAbdu, Esmat A. Doxorubicin supplemented with pravastatin in lipid nanoemulsion induces antineoplastic activity with limited hepatotoxicity and cardiotoxicity in tumor-bearing mice. Asian Journal of Pharmaceutical Research and Health Care. 2021;13:17-29.
16.Akindele AJ, Oludadepo GO, Amagon KI. Protective effect of carvedilol alone and coadministered with diltiazem and prednisolone on doxorubicin and 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats. Pharmacol Res Perspect. 2018;6(1):e00381.
17.Bartosz M, Kedziora J, Bartosz G. Antioxidant and prooxidant properties of captopril and enalapril. Free Radic Biol Med. 1997;23(5):729-35.
18.Abd El-Aziz MA, Othman AI, Amer M, El-Missiry MA. Potential protective role of angiotensin-converting enzyme inhibitors captopril and enalapril against adriamycin-induced acute cardiac and hepatic toxicity in rats. J Appl Toxicol. 2001;21(6):469-73.
19.Inglesi M, Nicola M, Fregnan GB, Bradamante S, Pagani G. Synthesis and free radical scavenging properties of the enantiomers of erdosteine. Farmaco (Societa chimica italiana : 1989). 1994;40(11):703-8.
20.Yagmurca M, Bas O, Mollaoglu H, et al. Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats. Arch Med Res. 2007;38(4):380-5.
21.Link G, Tirosh R, Pinson A, Hershko C. Role of iron in the potentiation of anthracycline cardiotoxicity: identification of heart cell mitochondria as a major site of iron-anthracycline interaction. J Lab Clin Med. 1996;127(3):272-8.
22.Saad SY, Najjar TA, Al-Rikabi AC. The preventive role of deferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats. Pharmacol Res. 2001;43(3):211-8.
23.Bulucu F, Ocal R, Karadurmus N, et al. Effects of N-acetylcysteine, deferoxamine and selenium on doxorubicin-induced hepatotoxicity. Biol Trace Elem Res. 2009;132(1-3):184-96.
24.Cengiz O, Baran M, Balcioglu E, et al. Use of selenium to ameliorate doxorubicin induced hepatotoxicity by targeting pro-inflammatory cytokines. Biotech Histochem. 2021;96(1):67-75.
25.Mirkov SM, Djordjevic AN, Andric NL, et al. Nitric oxide-scavenging activity of polyhydroxylated fullerenol, C60(OH)24. Nitric Oxide. 2004;11(2):201-7.
26.Grebowski J, Kazmierska P, Krokosz A. Fullerenols as a new therapeutic approach in nanomedicine. Biomed Res Int. 2013;2013:751913.
27.Jacevic V, Djordjevic A, Srdjenovic B, et al. Fullerenol nanoparticles prevents doxorubicin-induced acute hepatotoxicity in rats. Exp Mol Pathol. 2017;102(2):360-9.
28.Petrovic D, Seke M, Borovic ML, et al. Hepatoprotective effect of fullerenol/doxorubicin nanocomposite in acute treatment of healthy rats. Exp Mol Pathol. 2018;104(3):199-211.
29.Lawler JM, Barnes WS, Wu G, Song W, Demaree S. Direct antioxidant properties of creatine. Biochem Biophys Res Commun. 2002;290(1):47-52.
30.Bredahl EC, Hydock DS. Creatine supplementation and doxorubicin-induced skeletal muscle dysfunction: an ex vivo investigation. Nutr Cancer. 2017;69(4):607-15.
31.Aljobaily N, Viereckl MJ, Hydock DS, et al. Creatine Alleviates doxorubicin-induced liver damage by inhibiting liver fibrosis, inflammation, oxidative stress, and cellular senescence. Nutrients. 2020;13(1):41.
32.Villani F, Galimberti M, Monti E, et al. Effect of glutathione and N-acetylcysteine on in vitro and in vivo cardiac toxicity of doxorubicin. ree Radic Res Commun.1990;11(1-3):145-51.
33.Shen By, Chen C, Xu Yf, et al. Is the combinational administration of doxorubicin and glutathione a reasonable proposal? Acta Pharmacol Sin. 2019;40(5):699-709.
34.Daga M, de Graaf IAM, Argenziano M, et al. Glutathione-responsive cyclodextrin-nanosponges as drug delivery systems for doxorubicin: Evaluation of toxicity and transport mechanisms in the liver. Toxicol In Vitro. 2020;65:104800.
35.Rochette L, Ghibu S, Richard C, Zeller M, Cottin Y, Vergely C. Direct and indirect antioxidant properties of α-lipoic acid and therapeutic potential. Mol Nutr Food Res. 2013;57(1):114-25.
36.Anandakumar PP, Malarkodi SP, Sivaprasad TR, Saravanan GD. Antioxidant DL-alpha lipoic acid as an attenuator of adriamycin induced hepatotoxicity in rat model. Indian J Exp Biol. 2007;45(12):1045-9.
37.Xie C, Li X, Wu J, Liang Z, et al. Anti-inflammatory Activity of Magnesium Isoglycyrrhizinate Through Inhibition of Phospholipase A2/Arachidonic Acid Pathway. Inflammation. 2015;38(4):1639-48.
38.Wu Z, Zhang Y, Song T, et al. Magnesium isoglycyrrhizinate ameliorates doxorubicin-induced acute cardiac and hepatic toxicity via anti-oxidant and anti-apoptotic mechanisms in mice. Exp Ther Med. 2018;15(1):1005-12.
39.Green D, Hirsh J, Heit J, Prins M, Davidson B, Lensing AW. Low molecular weight heparin: a critical analysis of clinical trials. Pharmacol Rev. 1994;46(1):89-109.
40.Deepa PR, Varalakshmi P. Protective effect of low molecular weight heparin on oxidative injury and cellular abnormalities in adriamycin-induced cardiac and hepatic toxicity. Chem Biol Interact. 2003;146(2):201-10.
41.Hinkley JM, Morton AB, Ichinoseki-Sekine N, Huertas AM, Smuder AJ. exercise training prevents doxorubicin-induced mitochondrial dysfunction of the liver. Med Sci Sports Exerc. 2019;51(6):1106-15.
42.Alishahi A, Roshan VD, Hedayyati M. Pretreatment effects of regular aerobic training on the IGF system and hepatotoxicity induced by doxorubicin in rats. Asian Pac J Cancer Prev. 2013;14(12):7427-31.
43.Ferroni P, Zanzotto FM, Scarpato N, et al. Risk Assessment for Venous Thromboembolism in Chemotherapy-Treated Ambulatory Cancer Patients. Med Decis Making. 2017;37(2):234-42.
44.Gökçe AB, Eren B, Sağır D, Demirel Yılmaz B. A histopathological and stereological study of the effects of acetylsalicylic acid on doxorubicin-induced hepatotoxicity in mice. Biotech Histochem. 2021;96(4):251-6.
| Files | ||
| Issue | Vol 10, No 3 (Summer 2022) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/jpc.v10i3.10796 | |
| Keywords | ||
| Doxorubicin Adriamycin Hepatotoxicity Hepatoprotective | ||
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How to Cite
1.
Mahmoudi F, Elyasi S. None Herbal Agents as Preventive and Therapeutic Measures for Doxorubicin Induced Hepatotoxicity: A Comprehensive Review. J Pharm Care. 2022;10(3):151-166.
