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Review Articles

Toxic effects and molecular mechanism of doxorubicin on different organs – an update

, , & ORCID Icon
Pages 650-674 | Received 14 Oct 2020, Accepted 31 Mar 2021, Published online: 21 Apr 2021

References

  • Abdelrahman, A.M., et al., 2020. Effect of infliximab, a tumor necrosis factor-alpha inhibitor, on doxorubicin-induced nephrotoxicity in rats. Naunyn-Schmiedeberg's archives of pharmacology, 393 (1), 121–130.
  • Ahmed, O.M., et al., 2019. Camellia sinensis and epicatechin abate doxorubicin-induced hepatotoxicity in male Wistar rats via their modulatory effects on oxidative stress, inflammation, and apoptosis. Journal of applied pharmaceutical science, 9, 30–44.
  • Akgul, Y., et al., 2008. The methoxychlor metabolite, HPTE, directly inhibits the catalytic activity of cholesterol side-chain cleavage (P450scc) in cultured rat ovarian cells. Reproductive toxicology (Elmsford, N.Y.), 25 (1), 67–75.
  • Aksu, E.H., et al., 2019. Palliative effect of curcumin on doxorubicin-induced testicular damage in male rats . Journal of biochemical and molecular toxicology, 33 (10), e22384.
  • Alhowail, A.H., et al., 2019. Doxorubicin-induced neurotoxicity is associated with acute alterations in synaptic plasticity, apoptosis, and lipid peroxidation. Toxicology mechanisms and methods, 29 (6), 457–466.
  • Alonso, M., Medina, J.H., and Pozzo-Miller, L., 2004. ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learning & memory (Cold Spring Harbor, N.Y.), 11 (2), 172–178.
  • Aluise, C.D., et al., 2011. 2-Mercaptoethane sulfonate prevents doxorubicin-induced plasma protein oxidation and TNF-α release: implications for the reactive oxygen species-mediated mechanisms of chemobrain. Free radical biology & medicine, 50 (11), 1630–1638.
  • Arcamone, F., et al., 2000. Adriamycin, 14‐hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius. Biotechnology and bioengineering, 67 (6), 704–713.
  • Arunachalam, S., Pichiah, P.T., and Achiraman, S., 2013. Doxorubicin treatment inhibits PPARγ and may induce lipotoxicity by mimicking a type 2 diabetes-like condition in rodent models. FEBS letters, 587 (2), 105–110.
  • Arunachalam, S., et al., 2012. Adriamycin inhibits adipogenesis through the modulation of PPARγ and restoration of adriamycin-mediated inhibition of adipogenesis by PPARγ over-expression. Toxicology mechanisms and methods, 22 (7), 540–546.
  • Aryal, B., Jeong, J., and Rao, V.A., 2014. Doxorubicin-induced carbonylation and degradation of cardiac myosin binding protein C promote cardiotoxicity. Proceedings of the national academy of sciences of the United States of America, 111 (5), 2011–2016.
  • Ascensão, A., et al., 2005. Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces the development of cardiac apoptosis. American journal of physiology – heart and circulatory physiology, 289 (2), H722–H731.
  • Ashrafi, J., Roshan, V.D., and Mahjoub, S., 2012. Cardioprotective effects of aerobic regular exercise against doxorubicin-induced oxidative stress in rat. African journal of pharmacy and pharmacology, 6 (31), 2380–2388.
  • Baeza-Raja, B. and Muñoz-Cánoves, P., 2004. p38 MAPK-induced nuclear factor-kappaB activity is required for skeletal muscle differentiation: role of interleukin-6 . Molecular biology of the cell, 15 (4), 2013–2026.
  • Bahadır, A., et al., 2014. The role of nitric oxide in doxorubicin-induced cardiotoxicity: experimental study. Turkish journal of haematology, 31 (1), 68–74.
  • Ben-Aharon, I., et al., 2010. Doxorubicin-induced ovarian toxicity. Reproductive biology and endocrinology, 8, 20.
  • Berthiaume, J. and Wallace, K.B., 2007. Adriamycin-induced oxidative mitochondrial cardiotoxicity. Cell biology and toxicology, 23 (1), 15–25.
  • Bézaire, V. and Langin, D., 2009. Regulation of adipose tissue lipolysis revisited: symposium on ‘Frontiers in adipose tissue biology. The proceedings of the nutrition society, 68 (4), 350–360.
  • Biondo, L.A., et al., 2018. Metformin mitigates fibrosis and glucose intolerance induced by doxorubicin in subcutaneous adipose tissue. Frontiers in pharmacology, 9, 452.
  • Biondo, L.A., et al., 2016. Impact of doxorubicin treatment on the physiological functions of white adipose tissue. PLoS one, 11 (3), e0151548.
  • Bristow, M.R., et al., 1981. Dose-effect and structure-function relationships in doxorubicin cardiomyopathy. American heart journal, 102 (4), 709–718.
  • Brunengraber, D.Z., et al., 2003. Influence of diet on the modeling of adipose tissue triglycerides during growth. American journal of physiology. Endocrinology and metabolism, 285 (4), E917–E925.
  • Chen, X., et al., 2019. Protective effects of dioscin against doxorubicin-induced hepatotoxicity via regulation of Sirt1/FOXO1/NF-κb signal . Frontiers in pharmacology, 10, 1030.
  • Chiang, H.-C., et al., 2010. PI3 kinase signaling is involved in Abeta-induced memory loss in Drosophila. Proceedings of the national academy of sciences of the United States of America, 107 (15), 7060–7065.
  • Chichuk, T., Strashkevich, I., and Klebanov, G., 1999. Free radical mechanisms of low-intensive laser radiation. Vestnik Rossiiskoi Akademii Meditsinskikh Nauk, 2, 27–32.
  • Cianciolo, R., et al., 2013. Gene expression analysis and urinary biomarker assays reveal activation of tubulointerstitial injury pathways in a rodent model of chronic proteinuria (Doxorubicin nephropathy). Nephron. Experimental nephrology, 124 (1–2), 1–10.
  • Cortes-Funes, H. and Coronado, C., 2007. Role of anthracyclines in the era of targeted therapy. Cardiovascular toxicology, 7 (2), 56–60.
  • Cox, M.L. and Meek, D.W., 2010. Phosphorylation of serine 392 in p53 is a common and integral event during p53 induction by diverse stimuli. Cellular signalling, 22 (3), 564–571.
  • Cui, J., Shen, Y., and Li, R., 2013. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends in molecular medicine, 19 (3), 197–209.
  • Dai, H.-L., et al., 2016. p38 MAPK inhibition improves synaptic plasticity and memory in angiotensin II-dependent hypertensive mice. Scientific reports, 6, 27600.
  • Damiani, R.M., et al., 2016. Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone. Archives of toxicology, 90 (9), 2063–2076.
  • De Lima Junior, E.A., et al., 2016. Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle. Journal of cachexia, sarcopenia and muscle, 7 (5), 615–625.
  • Deng, S., et al., 2009. Differential roles of nitric oxide synthase isozymes in cardiotoxicity and mortality following chronic doxorubicin treatment in mice. Naunyn-Schmiedeberg's archives of pharmacology, 380 (1), 25–34.
  • Devadas, S., et al., 2003. Fas-stimulated generation of reactive oxygen species or exogenous oxidative stress sensitize cells to Fas-mediated apoptosis. Free radical biology & medicine, 35 (6), 648–661.
  • Devarajan, P., 2008. NGAL in acute kidney injury: from serendipity to utility. American journal of kidney diseases: the official journal of the national kidney foundation, 52 (3), 395–399.
  • Dirks‐Naylor, A.J., et al., 2014. Doxorubicin alters the mitochondrial dynamics machinery and mitophagy in the liver of treated animals. Fundamental & clinical pharmacology, 28 (6), 633–642.
  • Doroshow, J., et al., 1979. The effect of doxorubicin on hepatic and cardiac glutathione. Research communications in chemical pathology and pharmacology, 26 (2), 285–295.
  • Dowd, N.P., et al., 2001. Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo. The journal of clinical investigation, 108 (4), 585–590.
  • El-Agamy, D.S., et al., 2019. Pristimerin protects against doxorubicin-induced cardiotoxicity and fibrosis through modulation of Nrf2 and MAPK/NF-kB signaling pathways. Cancer management and research, 11, 47–61.
  • El‐Sayed, E.S.M., Mansour, A.M., and El‐Sawy, W.S., 2017. Protective effect of proanthocyanidins against doxorubicin‐induced nephrotoxicity in rats. Journal of biochemical and molecular toxicology, 31 (11), e21965.
  • Elsherbiny, N.M. and El-Sherbiny, M., 2014. Thymoquinone attenuates doxorubicin-induced nephrotoxicity in rats: role of Nrf2 and NOX4. Chemico-biological interactions, 223, 102–108.
  • Ezzat, S.M., et al., 2016. The cardenolide glycoside acovenoside a affords protective activity in doxorubicin-induced cardiotoxicity in mice. The journal of pharmacology and experimental therapeutics, 358 (2), 262–270.
  • Ferrans, V., et al., 1997. Pathogenesis and prevention of doxorubicin cardiomyopathy. Tsitologiia, 39 (10), 928–937.
  • Fornari, F.A., et al., 1994. Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells. Molecular pharmacology, 45 (4), 649–656.
  • Fouad, A.A., et al., 2013. Cardioprotective effect of cannabidiol in rats exposed to doxorubicin toxicity. Environmental toxicology and pharmacology, 36 (2), 347–357.
  • Fulda, S. and Debatin, K.-M., 2006. 5-Aza-2'-deoxycytidine and IFN-gamma cooperate to sensitize for TRAIL-induced apoptosis by upregulating caspase-8. Oncogene, 25 (37), 5125–5133.
  • Goffart, S., Von Kleist-Retzow, J.-C., and Wiesner, R.J., 2004. Regulation of mitochondrial proliferation in the heart: power-plant failure contributes to cardiac failure in hypertrophy. Cardiovascular research, 64 (2), 198–207.
  • Goh, F.G. and Midwood, K.S., 2012. Intrinsic danger: activation of Toll-like receptors in rheumatoid arthritis. Rheumatology (Oxford, England), 51 (1), 7–23.
  • Goormaghtigh, E., et al., 1980. Evidence of a complex between adriamycin derivatives and cardiolipin: possible role in cardiotoxicity. Biochemical pharmacology, 29 (21), 3003–3010.
  • Gratia, S., et al., 2012. Inhibition of AMPK signalling by doxorubicin: at the crossroads of the cardiac responses to energetic, oxidative, and genotoxic stress. Cardiovascular research, 95 (3), 290–299.
  • Guerra, J., et al., 2005. Plasma nitric oxide levels used as an indicator of doxorubicin-induced cardiotoxicity in rats. The hematology journal, 5 (7), 584–588.
  • Gurel, C., et al., 2019. Fluvastatin attenuates doxorubicin-induced testicular toxicity in rats by reducing oxidative stress and regulating the blood–testis barrier via mTOR signaling pathway. Human & experimental toxicology, 38 (12), 1329–1343.
  • Guven, C., Sevgiler, Y., and Taskin, E., 2018. Mitochondrial dysfunction associated with doxorubicin. Mitochondrial diseases, 3, 323.
  • Han, M.-K., et al., 2008. SIRT1 regulates apoptosis and Nanog expression in mouse embryonic stem cells by controlling p53 subcellular localization. Cell stem cell, 2 (3), 241–251.
  • Heart, E.A., et al., 2016. Mechanisms of doxorubicin toxicity in pancreatic β-cells. Toxicological sciences: an official journal of the society of toxicology, 152 (2), 395–405.
  • Horwood, J.M., et al., 2006. Signalling mechanisms mediated by the phosphoinositide 3-kinase/Akt cascade in synaptic plasticity and memory in the rat. The European journal of neuroscience, 23 (12), 3375–3384.
  • Huang, J., et al., 2011. Regulator of G protein signaling 6 mediates doxorubicin-induced ATM and p53 activation by a reactive oxygen species-dependent mechanism. Cancer research, 71 (20), 6310–6319.
  • Ichikawa, Y., et al., 2014. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. The journal of clinical investigation, 124 (2), 617–630.
  • Imam, F., et al., 2018. Apremilast prevent doxorubicin-induced apoptosis and inflammation in heart through inhibition of oxidative stress mediated activation of NF-κB signaling pathways. Pharmacological reports, 70 (5), 993–1000.
  • Injac, R., et al., 2008. Potential hepatoprotective effects of fullerenol C60(OH)24 in doxorubicin-induced hepatotoxicity in rats with mammary carcinomas. Biomaterials, 29 (24–25), 3451–3460.
  • Jalali, A.S. and Hasanzadeh, S., 2013. Crataegus monogyna fruit aqueous extract as a protective agent against doxorubicin-induced reproductive toxicity in male rats. Avicenna journal of phytomedicine, 3, 159.
  • Janani, C. and Kumari, B.R., 2015. PPAR gamma gene-a review. Diabetes & metabolic syndrome, 9 (1), 46–50.
  • Jequier, A., 2000. Primary testicular disease: a common cause of male infertility. Male infertility, 90, 121–124.
  • Jin, X., et al., 2013. Genetic deficiency of adiponectin protects against acute kidney injury. Kidney international, 83 (4), 604–614.
  • Johnson, G.L. and Lapadat, R., 2002. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science (New York, N.Y.), 298 (5600), 1911–1912.
  • Kansanen, E., et al., 2013. The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox biology, 1, 45–49.
  • Karale, S., Yamuna, P., and Kamath, J., 2019. Protective effect of capsaicin against doxorubicin induced cardiotoxicity in experimental rats. Indian journal of pharmaceutical education and research, 54 (1), 95–100.
  • Kassner, N., et al., 2008. Carbonyl reductase 1 is a predominant doxorubicin reductase in the human liver. Drug metabolism and disposition: the biological fate of chemicals, 36 (10), 2113–2120.
  • Katoh, C., et al., 2002. Assessment of quantitative dual-parameter flow cytometric analysis for the evaluation of testicular toxicity using cyclophosphamide- and ethinylestradiol-treated rats. The journal of toxicological sciences, 27 (2), 87–96.
  • Keeney, J.T., et al., 2015. Superoxide induces protein oxidation in plasma and TNF-α elevation in macrophage culture: insights into mechanisms of neurotoxicity following doxorubicin chemotherapy. Cancer letters, 367 (2), 157–161.
  • Kelly, A., et al., 2003. Activation of p38 plays a pivotal role in the inhibitory effect of lipopolysaccharide and interleukin-1 beta on long term potentiation in rat dentate gyrus. The journal of biological chemistry, 278 (21), 19453–19462.
  • Khalilzadeh, M., et al., 2018. Protective effects of magnesium sulfate against doxorubicin induced cardiotoxicity in rats. Life sciences, 207, 436–441.
  • Khames, A., et al., 2017. Ameliorative effects of sildenafil and/or febuxostat on doxorubicin-induced nephrotoxicity in rats. European journal of pharmacology, 805, 118–124.
  • Khames, A., et al., 2019. Nicorandil combats doxorubicin-induced nephrotoxicity via amendment of TLR4/P38 MAPK/NFκ-B signaling pathway. Chemico-biological interactions, 311, 108777.
  • Kim, D.-S., et al., 2006. Protective effect of calceolarioside on adriamycin-induced cardiomyocyte toxicity. European journal of pharmacology, 541 (1–2), 24–32.
  • Kim, J.-C., Kim, K.-H., and Chung, M.-K., 1999. Testicular cytotoxicity of DA-125, a new anthracycline anticancer agent, in rats. Reproductive toxicology (Elmsford, N.Y.), 13 (5), 391–397.
  • Knott, A.B., et al., 2008. Mitochondrial fragmentation in neurodegeneration. Nature reviews. Neuroscience, 9 (7), 505–518.
  • Koul, H.K., Pal, M., and Koul, S., 2013. Role of p38 MAP kinase signal transduction in solid tumors. Genes & cancer, 4 (9–10), 342–359.
  • Kumar, A., et al., 2004. Nuclear factor-kappaB: its role in health and disease. Journal of molecular medicine (Berlin, Germany), 82 (7), 434–448.
  • Lass, A., et al., 2006. Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin–Dorfman syndrome. Cell metabolism, 3 (5), 309–319.
  • Lee, K.M., et al., 2012. Melatonin attenuates doxorubicin‐induced testicular toxicity in rats. Andrologia, 44, 796–803.
  • Lee, V.W. and Harris, D.C., 2011. Adriamycin nephropathy: a model of focal segmental glomerulosclerosis. Nephrology (Carlton, Vic.), 16 (1), 30–38.
  • Li, D.L. and Hill, J.A., 2014. Cardiomyocyte autophagy and cancer chemotherapy. Journal of molecular and cellular cardiology, 71, 54–61.
  • Liu, J., et al., 2008. ERKs/p53 signal transduction pathway is involved in doxorubicin-induced apoptosis in H9c2 cells and cardiomyocytes. American journal of physiology. Heart and circulatory physiology, 295 (5), H1956–H1965.
  • Luderer, U., 2014. Ovarian toxicity from reactive oxygen species. In: Vitamins & hormones. New York, NY: Elsevier, 99–127. [AQ]
  • Luo, J.-L., Kamata, H., and Karin, M., 2005. IKK/NF-kappaB signaling: balancing life and death-a new approach to cancer therapy . The journal of clinical investigation, 115 (10), 2625–2632.
  • Ma, Q., 2013. Role of nrf2 in oxidative stress and toxicity. Annual review of pharmacology and toxicology, 53, 401–426.
  • Mantovani, A., et al., 2008. Cancer-related inflammation. Nature, 454 (7203), 436–444.
  • Markin, A., et al., 1997. Lipid peroxidation and activity of diagnostically significant enzymes in cosmonauts after flights of various durations. Aviakosmicheskaia i Ekologicheskaia Meditsina = Aerospace and environmental medicine, 31 (3), 14–18.
  • Maruyama, S., et al., 2011. Adiponectin ameliorates doxorubicin-induced cardiotoxicity through Akt protein-dependent mechanism. The journal of biological chemistry, 286 (37), 32790–32800.
  • Minotti, G., et al., 2004. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacological reviews, 56 (2), 185–229.
  • Mitry, M.A. and Edwards, J.G., 2016. Doxorubicin induced heart failure: phenotype and molecular mechanisms. International journal of cardiology. Heart & vasculature, 10, 17–24.
  • Miyata, S., et al., 2010. Anti-Fas gene therapy prevents doxorubicin-induced acute cardiotoxicity through mechanisms independent of apoptosis. The American journal of pathology, 176 (2), 687–698.
  • Mohamed, R.H., Karam, R.A., and Amer, M.G., 2011. Epicatechin attenuates doxorubicin-induced brain toxicity: critical role of TNF-α, iNOS and NF-κB. Brain research bulletin, 86 (1–2), 22–28.
  • Mok, K.-W., Mruk, D.D., and Cheng, C.Y., 2014. rpS6 regulates blood-testis barrier dynamics through Akt-mediated effects on MMP-9 . Journal of cell science, 127 (Pt 22), 4870–4882.
  • Mukherjee, S., et al., 2003. Protection against acute adriamycin-induced cardiotoxicity by garlic: role of endogenous antioxidants and inhibition of TNF-alpha expression. BMC pharmacology, 3, 16.
  • Mukhopadhyay, P., et al., 2009. Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. American journal of physiology. Heart and circulatory physiology, 296 (5), H1466–H1483.
  • Müller, M., et al., 1998. p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. The journal of experimental medicine, 188 (11), 2033–2045.
  • Nakamura, T., et al., 2000. Fas-mediated apoptosis in adriamycin-induced cardiomyopathy in rats: in vivo study. Circulation, 102 (5), 572–578.
  • Naska, S., et al., 2006. An essential role for the integrin-linked kinase-glycogen synthase kinase-3 beta pathway during dendrite initiation and growth. The journal of neuroscience: the official journal of the society for neuroscience, 26 (51), 13344–13356.
  • Nelson, D.P., et al., 2000. Proinflammatory consequences of transgenic fas ligand expression in the heart. The journal of clinical investigation, 105 (9), 1199–1208.
  • Nishi, K., et al., 2018. Doxorubicin-induced female reproductive toxicity: an assessment of ovarian follicular apoptosis, cyclicity and reproductive tissue histology in Wistar rats. Drug and chemical toxicology, 41 (1), 72–81.
  • Nozaki, N., et al., 2004. Modulation of doxorubicin-induced cardiac dysfunction in toll-like receptor-2–knockout mice. Circulation, 110 (18), 2869–2874.
  • Oh, J., et al., 2020. Atorvastatin protects cardiomyocyte from doxorubicin toxicity by modulating survivin expression through FOXO1 inhibition. Journal of molecular and cellular cardiology, 138, 244–255.
  • Pal, S., Ahir, M., and Sil, P.C., 2012. Doxorubicin-induced neurotoxicity is attenuated by a 43-kD protein from the leaves of Cajanus indicus L. via NF-κB and mitochondria dependent pathways. Free radical research, 46 (6), 785–798.
  • Pallepati, P. and Averill-Bates, D., 2010. Mild thermotolerance induced at 40 degrees C increases antioxidants and protects HeLa cells against mitochondrial apoptosis induced by hydrogen peroxide: role of p53. Archives of biochemistry and biophysics, 495 (2), 97–111.
  • Pallepati, P. and Averill-Bates, D.A., 2011. Mild thermotolerance induced at 40 °C protects HeLa cells against activation of death receptor-mediated apoptosis by hydrogen peroxide . Free radical biology & medicine, 50 (6), 667–679.
  • Park, E.-J., et al., 2012. Doxorubicin induces cytotoxicity through upregulation of perk–dependent ATF3. PLoS One, 7 (9), e44990.
  • Parker, M.A., King, V., and Howard, K.P., 2001. Nuclear magnetic resonance study of doxorubicin binding to cardiolipin containing magnetically oriented phospholipid bilayers. Biochimica et biophysica acta (Bba) – Biomembranes, 1514 (2), 206–216.
  • Pereira, G.C., et al., 2011. Drug-induced cardiac mitochondrial toxicity and protection: from doxorubicin to carvedilol. Current pharmaceutical design, 17 (20), 2113–2129.
  • Pointon, A.V., et al., 2010. Doxorubicin in vivo rapidly alters expression and translation of myocardial electron transport chain genes, leads to ATP loss and caspase 3 activation. PLoS one, 5 (9), e12733.
  • Prasanna, P.L., Renu, K., and Abilash, V., 2020. New molecular and biochemical insights of doxorubicin-induced hepatotoxicity. Life sciences, 250, 117599.
  • Pugazhendhi, A., et al., 2018. Toxicity of soxorubicin (Dox) to different experimental organ systems. Life sciences, 200, 26–30.
  • Qian, H., Yang, Y., and Wang, X., 2011. Curcumin enhanced adriamycin-induced human liver-derived hepatoma G2 cell death through activation of mitochondria-mediated apoptosis and autophagy. European journal of pharmaceutical sciences: official journal of the European federation for pharmaceutical sciences, 43 (3), 125–131.
  • Quiles, J.L., et al., 2002. Antioxidant nutrients and adriamycin toxicity. Toxicology, 180 (1), 79–95.
  • Ren, X., et al., 2016. Dalbergioidin ameliorates doxorubicin-induced renal fibrosis by suppressing the TGF-β signal pathway. Mediators of inflammation, 2016, 5147571.
  • Renu, K. and Gopalakrishnan, A.V., 2019. Deciphering the molecular mechanism during doxorubicin-mediated oxidative stress, apoptosis through Nrf2 and PGC-1α in a rat testicular milieu. Reproductive biology, 19 (1), 22–37.
  • Renu, K., et al., 2018. Molecular mechanism of doxorubicin-induced cardiomyopathy – an update. European journal of pharmacology, 818, 241–253.
  • Renu, K., et al., 2017. Adriamycin-induced cardiomyopathy can serve as a model for diabetic cardiomyopathy – a hypothesis. Asian Pacific journal of tropical biomedicine, 7 (11), 1041–1045.
  • Renu, K., et al., 2019. Elevated lipolysis in adipose tissue by doxorubicin via PPARα activation associated with hepatic steatosis and insulin resistance. European journal of pharmacology, 843, 162–176.
  • Richter, K.S., et al., 2007. Relationship between endometrial thickness and embryo implantation, based on 1,294 cycles of in vitro fertilization with transfer of two blastocyst-stage embryos. Fertility and sterility, 87 (1), 53–59.
  • Rivankar, S., 2014. An overview of doxorubicin formulations in cancer therapy. Journal of cancer research and therapeutics, 10 (4), 853–858.
  • Rizk, H.A., Masoud, M.A., and Maher, O.W., 2017. Prophylactic effects of ellagic acid and rosmarinic acid on doxorubicin‐induced neurotoxicity in rats. Journal of biochemical and molecular toxicology, 31 (12), e21977.
  • Roti, E.C.R., et al., 2012. Acute doxorubicin insult in the mouse ovary is cell-and follicle-type dependent. PLoS One, 7 (8), e42293.
  • Ryter, S., et al., 2007. Mechanisms of cell death in oxidative stress. Antioxidants & redox signaling, 9 (1), 49–89.
  • Saeed, N.M., et al., 2015. Epigallocatechin-3-gallate pretreatment attenuates doxorubicin-induced cardiotoxicity in rats: a mechanistic study. Biochemical pharmacology, 95 (3), 145–155.
  • Saely, C.H., Geiger, K., and Drexel, H., 2012. Brown versus white adipose tissue: a mini-review. Gerontology, 58 (1), 15–23.
  • Salgarello, M., Visconti, G., and Barone-Adesi, L., 2013. Interlocking circumareolar suture with undyed polyamide thread: a personal experience. Aesthetic plastic surgery, 37 (5), 1061–1062.
  • Santos-Alves, E., et al., 2019. Physical exercise positively modulates DOX-induced hepatic oxidative stress, mitochondrial dysfunction and quality control signaling. Mitochondrion, 47, 103–113.
  • Sardi, I., et al., 2014. Delivery of doxorubicin across the blood-brain barrier by ondansetron pretreatment: a study in vitro and in vivo. Cancer letters, 353 (2), 242–247.
  • Scaglia, F., 2010. The role of mitochondrial dysfunction in psychiatric disease. Developmental disabilities research reviews, 16 (2), 136–143.
  • Selvakumar, E., et al., 2005. Beneficial effects of DL-α-lipoic acid on cyclophosphamide-induced oxidative stress in mitochondrial fractions of rat testis. Chemico-biological interactions, 152 (1), 59–66.
  • Sheibani, M., et al., 2020. Cardioprotective effects of dapsone against doxorubicin-induced cardiotoxicity in rats. Cancer chemotherapy and pharmacology, 85 (3), 563–569.
  • Shi, Y., et al., 2011. Mechanisms and management of doxorubicin cardiotoxicity. Herz, 36 (4), 296–305.
  • Sikka, S.C., 2004. Andrology lab corner: role of oxidative stress and antioxidants in andrology and assisted reproductive technology. Journal of andrology, 25 (1), 5–18.
  • Singal, P., et al., 2000. Adriamycin-induced heart failure: mechanisms and modulation. Molecular and cellular biochemistry, 207 (1/2), 77–86.
  • Siveski-Iliskovic, N., et al., 1995. Probucol protects against adriamycin cardiomyopathy without interfering with its antitumor effect. Circulation, 91 (1), 10–15.
  • Smirnova, E., et al., 2006. ATGL has a key role in lipid droplet/adiposome degradation in mammalian cells. EMBO reports, 7 (1), 106–113.
  • Subapriya, R., et al., 2002. Oxidant-antioxidant status in patients with oral squamous cell carcinomas at different intraoral sites. Clinical biochemistry, 35 (6), 489–493.
  • Tacar, O., Sriamornsak, P., and Dass, C.R., 2013. Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. The journal of pharmacy and pharmacology, 65 (2), 157–170.
  • Takanaga, H., et al., 1998. Efflux transport of tolbutamide across the blood-brain barrier. The journal of pharmacy and pharmacology, 50 (9), 1027–1033.
  • Taskin, E. and Dursun, N., 2015. Recovery of adriamycin induced mitochondrial dysfunction in liver by selenium. Cytotechnology, 67 (6), 977–986.
  • Tham, Y.K., et al., 2015. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Archives of toxicology, 89 (9), 1401–1438.
  • Thandavarayan, R.A., et al., 2015. Schisandrin B prevents doxorubicin induced cardiac dysfunction by modulation of DNA damage, oxidative stress and inflammation through inhibition of MAPK/p53 signaling. PLoS One, 10 (3), e0119214.
  • Thomson, T.C., Fitzpatrick, K.E., and Johnson, J., 2010. Intrinsic and extrinsic mechanisms of oocyte loss. Molecular human reproduction, 16 (12), 916–927.
  • Thorn, C.F., et al., 2011. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenetics and genomics, 21 (7), 440–446.
  • Tian, M., et al., 2018. Adiponectin attenuates kidney injury and fibrosis in deoxycorticosterone acetate-salt and angiotensin II-induced CKD mice. American journal of physiology. Renal physiology, 315 (3), F558–F571.
  • Timm, K.N. and Tyler, D.J., 2020. The role of AMPK activation for cardioprotection in doxorubicin-induced cardiotoxicity. Cardiovascular drugs and therapy, 34 (2), 215–255.
  • Torti, F.M., et al., 1986. Cardiotoxicity of epirubicin and doxorubicin: assessment by endomyocardial biopsy. Cancer research, 46 (7), 3722–3727.
  • Trifilieff, P., et al., 2007. Biphasic ERK1/2 activation in both the hippocampus and amygdala may reveal a system consolidation of contextual fear memory. Neurobiology of learning and memory, 88 (4), 424–434.
  • Vernet, P., Aitken, R.J., and Drevet, J.R., 2004. Antioxidant strategies in the epididymis. Molecular and cellular endocrinology, 216 (1–2), 31–39.
  • Viatour, P. , et al., 2005. Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. Trends in biochemical sciences, 30 (1), 43–52.
  • Vyas, D., Laput, G., and Vyas, A.K., 2014. Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis. OncoTargets and therapy, 7, 1015–1023.
  • Walczak, H. and Krammer, P.H., 2000. The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Experimental cell research, 256 (1), 58–66.
  • Wallace, W.H.B. and Kelsey, T.W., 2010. Human ovarian reserve from conception to the menopause. PLoS one, 5 (1), e8772.
  • Wang, Y.D., et al., 2008. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology (Baltimore, Md.), 48 (5), 1632–1643.
  • Ward, J.A., et al., 1988. Delayed effects of doxorubicin on spermatogenesis and endocrine function in rats. Reproductive toxicology (Elmsford, N.Y.), 2 (2), 117–126.
  • Wardill, H.R., et al., 2016. Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction. International journal of cancer, 139 (12), 2635–2645.
  • West, J.D. and Marnett, L.J., 2006. Endogenous reactive intermediates as modulators of cell signaling and cell death. Chemical research in toxicology, 19 (2), 173–194.
  • Wu, R., et al., 2016. Doxorubicin toxicity changes myocardial energy metabolism in rats. Chemico-biological interactions, 244, 149–158.
  • Xiao, B., et al., 2019. The true colors of autophagy in doxorubicin-induced cardiotoxicity. Oncology letters, 18 (3), 2165–2172.
  • Xiao, J., et al., 2012. Kaempferol protects against doxorubicin-induced cardiotoxicity in vivo and in vitro. Toxicology, 292 (1), 53–62.
  • Xin, Y.F., et al., 2012. Protective effect of Lycium barbarum polysaccharides against doxorubicin-induced testicular toxicity in rats. Phytotherapy research : PTR, 26 (5), 716–721.
  • Xu, H., et al., 2016. mTOR/P70S6K promotes spermatogonia proliferation and spermatogenesis in Sprague Dawley rats. Reproductive biomedicine online, 32 (2), 207–217.
  • Yao, B., Rieanrakwong, D., and Kawaminami, M., 2009. Testicular annexin A5 expression augmented by experimental cryptorchidism and could affect germ cell apoptosis in rats. Urology, 73 (6), 1412–1416.
  • Yao, P.-A., et al., 2018. Alleviation of doxorubicin-induced hepatic toxicity with fermented Cordyceps sinensis via regulating hepatic energy metabolism in rats. Pharmacognosy magazine, 14 (56), 283.
  • Ye, H., et al., 2013. Resistin production from adipose tissue is decreased in db/db obese mice, and is reversed by rosiglitazone. PLoS one, 8 (6), e65543.
  • Yoshida, K. and Miki, Y., 2010. The cell death machinery governed by the p53 tumor suppressor in response to DNA damage. Cancer science, 101 (4), 831–835.
  • Zhang, J., et al., 1998. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature, 392 (6673), 296–300.
  • Zhang, T., et al., 2017a. Effect of doxorubicin-induced ovarian toxicity on mouse ovarian granulosa cells. Regulatory toxicology and pharmacology, 86, 1–10.
  • Zhang, T., et al., 2016. The comparison of animal models for premature ovarian failure established by several different source of inducers. Regulatory toxicology and pharmacology, 81, 223–232.
  • Zhang, Y., et al., 2017b. Protective effects of dioscin against doxorubicin-induced nephrotoxicity via adjusting FXR-mediated oxidative stress and inflammation. Toxicology, 378, 53–64.
  • Zhao, L., et al., 2018. Protective effect of dioscin against doxorubicin-induced cardiotoxicity via adjusting microRNA-140-5p-mediated myocardial oxidative stress. Redox biology, 16, 189–198.

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