Abstract
Doxorubicin (DOX) is a widely used anthracycline antibiotic for the management of carcinoma. However, it is associated with cardiotoxicity. Fisetin is a plant flavonoid reported to have anti-inflammatory and antiapoptotic potential. To evaluate the cardioprotective potential of fisetin in DOX-induced cardiotoxicity in experimental rats. Sprague–Dawley rats were pre-treated with either fisetin (10, 20 and 40 mg/kg) or sitagliptin (10 mg/kg, p.o.) for 7 days. Cardiac toxicity was induced in rats (except the normal group) by doxorubicin (15 mg/kg i.p.) on 8th day. Various behavioral, biochemical, molecular and histological parameters were assessed in cardiac tissue. DOX-induced alterations in electrocardiographic, hemodynamic and left ventricular function were significantly (p < 0.05) inhibited by fisetin (20 and 40 mg/kg) treatment. Fisetin significantly decrease (p < 0.05) DOX-induced elevated serum CK-MB, LDH, AST, ALT and ALP levels. DOX-induced elevated cardiac oxido-nitrosative (SOD, GSH, MDA and NO) was significantly inhibited (p < 0.05) by fisetin. Up-regulated cardiac caspase-3, COX-II, cTn-I, iNOs, TNF-α, and IL-1β mRNA, as well as protein expressions were significantly decreased (p < 0.05) by fisetin treatment. It also significantly (p < 0.05) attenuated DOX-induced histopathological alterations in cardiac tissue. In conclusion, the fisetin exerts its cardioprotective potential against DOX-induced toxicity via inhibition of multiple pathways including oxidative stress (SOD, GSH, MDA and NO), inflammation (COX-II, TNF-α, and IL-1β), and apoptosis (Caspase-3). Therefore, fisetin can be considered as a potential cardioprotective agent during the management of carcinoma using doxorubicin anthracyclines.
Graphical abstract
Similar content being viewed by others
Abbreviations
- ALT:
-
Alanine transaminase
- ALP:
-
Alkaline phosphatase
- ANP:
-
Atrial natriuretic peptide
- AST:
-
Aspartate aminotransferase
- BNP:
-
Brain natriuretic peptide
- BPM:
-
Blood pressure per minute
- cTn-I:
-
Cardiac troponin I
- CK-MB:
-
Creatine kinase-MB
- COX-II:
-
Cyclooxygenase-II
- DNA:
-
Deoxyribonucleic acid
- DBP:
-
Diastolic blood pressure
- iNOs:
-
Inducible nitric oxide
- IL 1β:
-
Interleukin 1-β
- LDH:
-
Lactate dehydrogenase
- LVEDP:
-
Left ventricular end-diastolic pressure
- LVESP:
-
Left ventricular end-systolic pressure
- MABP:
-
Mean arterial blood pressure
- MDA:
-
Malondialdehyde
- NO:
-
Nitric oxide
- ROS:
-
Reactive oxygen species
- GSH:
-
Reduced glutathione
- RT-PCR:
-
Reverse transcription-polymerase chain reaction
- RNA:
-
Ribonucleic acid
- SOD:
-
Superoxide dismutase
- SBP:
-
Systolic blood pressure
- TNF-α:
-
Tumor necrosis factor-α
References
Injac R, Perse M, Obermajer N, Djordjevic-Milic V, Prijatelj M, Djordjevic A et al (2008) Potential hepatoprotective effects of fullerenol C60(OH)24 in doxorubicin-induced hepatotoxicity in rats with mammary carcinomas. Biomaterials 29:3451–3460
Ayla S, Seckin I, Tanriverdi G, Cengiz M, Eser M, Soner BC et al (2011) Doxorubicin induced nephrotoxicity: protective effect of nicotinamide. Int J Cell Biol 2011:390238
Pecoraro M, Del Pizzo M, Marzocco S, Sorrentino R, Ciccarelli M, Iaccarino G et al (2016) Inflammatory mediators in a short-time mouse model of doxorubicin-induced cardiotoxicity. Toxicol Appl Pharmacol 293:44–52
Abd El-Aziz TA, Mohamed RH, Pasha HF, Abdel-Aziz HR (2012) Catechin protects against oxidative stress and inflammatory-mediated cardiotoxicity in adriamycin-treated rats. Clin Exp Med 12:233–240
Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL (2012) Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 52:1213–1225
Liang S, Brundage RC, Jacobson PA, Blaes A, Kirstein MN (2016) Pharmacokinetic-pharmacodynamic modelling of acute N-terminal pro B-type natriuretic peptide after doxorubicin infusion in breast cancer. Br J Clin Pharmacol 82:773–783
Vachhani P, Shin S, Baron J, Thompson JE, Wetzler M, Griffiths EA et al (2017) Dexrazoxane for cardioprotection in older adults with acute myeloid leukemia. Leuk Res Rep 7:36–39
Al-Kuraishy HM, Khaleel KJ, Mohammed MA (2015) Significant attenuation and amelioration effects of labetalol in doxorubicin-induced cardiotoxicity: an animal model study. Cardiovasc Surgery 3:25–29
Alkuraishy HM, Al-Gareeb AI, Al-hussaniy HA (2017) Doxorubicin-induced cardiotoxicity: molecular mechanism and protection by conventional drugs and natural products. Inter J Clin Oncol Cancer Res 2:31–44
Oyagbemi AA, Omobowale TO, Olopade JO, Farombi EO (2017) Kolaviron and Garcinia kola attenuate doxorubicin-induced cardiotoxicity in Wistar rats. J Complement Integr Med 15 https://doi.org/10.1515/jcim-2016-0168
van Acker F (2001) New synthetic flavonoids as potent protectors against doxorubicin-induced cardiotoxicity. Free Radic Biol Med 31:31–37
Kandhare A, Raygude K, Ghosh P, Bodhankar S (2011) The ameliorative effect of fisetin, a bioflavonoid, on ethanol-induced and pylorus ligation-induced gastric ulcer in rats. Int J Green Pharm 5:236–243
Raygude KS, Kandhare AD, Ghosh P, Bodhankar SL (2012) Anticonvulsant effect of fisetin by modulation of endogenous biomarkers. Biomed Prev Nutr 2:215–222
Prasath GS, Subramanian SP (2014) Antihyperlipidemic effect of fisetin, a bioflavonoid of strawberries, studied in streptozotocin-induced diabetic rats. J Biochem Mol Toxicol 28:442–449
Laughton MJ, Evans PJ, Moroney MA, Hoult JR, Halliwell B (1991) Inhibition of mammalian 5-lipoxygenase and cyclo-oxygenase by flavonoids and phenolic dietary additives. Relationship to antioxidant activity and to iron ion-reducing ability. Biochem Pharmacol 42:1673–1681
Kim JH, Kim MY, Kim JH, Cho JY (2015) Fisetin Suppresses Macrophage-Mediated Inflammatory Responses by Blockade of Src and Syk. Biomol Ther 23:414–420
Shanmugam K, Ravindran S, Kurian GA, Rajesh M (2018) Fisetin confers cardioprotection against myocardial ischemia reperfusion injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction and inhibiting glycogen synthase kinase 3beta activity. Oxid Med Cell Longev. 2018:9173436
Kelleni MT, Amin EF, Abdelrahman AM (2015) Effect of metformin and sitagliptin on doxorubicin-induced cardiotoxicity in rats: impact of oxidative stress, inflammation, and apoptosis. J Toxicol 2015:424813
Kandhare AD, Ghosh P, Ghule AE, Bodhankar SL (2013) Elucidation of molecular mechanism involved in neuroprotective effect of coenzyme Q10 in alcohol-induced neuropathic pain. Fundam Clin Pharmacol 27:603–622
Visnagri A, Kandhare AD, Bodhankar SL (2015) Renoprotective effect of berberine via intonation on apoptosis and mitochondrial-dependent pathway in renal ischemia reperfusion-induced mutilation. Ren Fail 37:482–493
Kandhare AD, Ghosh P, Bodhankar SL (2014) Naringin, a flavanone glycoside, promotes angiogenesis and inhibits endothelial apoptosis through modulation of inflammatory and growth factor expression in diabetic foot ulcer in rats. Chem Biol Interact 219:101–112
Visnagri A, Kandhare AD, Chakravarty S, Ghosh P, Bodhankar SL (2014) Hesperidin, a flavanoglycone attenuates experimental diabetic neuropathy via modulation of cellular and biochemical marker to improve nerve functions. Pharm Biol 52:814–828
Visnagri A, Kandhare AD, Ghosh P, Bodhankar SL (2013) Endothelin receptor blocker bosentan inhibits hypertensive cardiac fibrosis in pressure overload-induced cardiac hypertrophy in rats. Cardiovasc Endocrinol 2:85–97
Chen JY, Hu RY, Chou HC (2013) Quercetin-induced cardioprotection against doxorubicin cytotoxicity. J Biomed Sci 20:95
Adedara IA, Farombi EO (2014) Influence of kolaviron and vitamin E on ethylene glycol monoethyl ether-induced haematotoxicity and renal apoptosis in rats. Cell Biochem Funct 32:31–38
Altena R, Perik PJ, van Veldhuisen DJ, de Vries EG, Gietema JA (2009) Cardiovascular toxicity caused by cancer treatment: strategies for early detection. Lancet Oncol 10:391–399
Jensen BV, Skovsgaard T, Nielsen SL (2002) Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol 13:699–709
Hadi N, Yousif NG, Al-amran FG, Huntei NK, Mohammad BI, Ali SJ (2012) Vitamin E and telmisartan attenuates doxorubicin induced cardiac injury in rat through down regulation of inflammatory response. BMC Cardiovasc Disord 12:63
Herman E, Mhatre R, Lee IP, Vick J, Waravdekar VS (1971) A comparison of the cardiovascular actions of daunomycin, adriamycin and N-acetyldaunomycin in hamsters and monkeys. Pharmacology 6:230–241
Fu X, Kong L, Tang M, Zhang J, Zhou X, Li G et al (2014) Protective effect of ocotillol against doxorubicininduced acute and chronic cardiac injury. Mol Med Rep 9:360–364
Sahu BD, Kalvala AK, Koneru M, Mahesh Kumar J, Kuncha M, Rachamalla SS et al (2014) Ameliorative effect of fisetin on cisplatin-induced nephrotoxicity in rats via modulation of NF-κB activation and antioxidant defence. PLoS ONE 9:e105070
Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229
Zhou S, Palmeira CM, Wallace KB (2001) Doxorubicin-induced persistent oxidative stress to cardiac myocytes. Toxicol Lett 121:151–157
Goswami S, Kandhare A, Zanwar AA, Hegde MV, Bodhankar SL, Shinde S et al (2016) Oral L-glutamine administration attenuated cutaneous wound healing in Wistar rats. Int Wound J 13:116–124
Honmore V, Kandhare A, Zanwar AA, Rojatkar S, Bodhankar S, Natu A (2015) Artemisia pallens alleviates acetaminophen induced toxicity via modulation of endogenous biomarkers. Pharm Biol 53:571–581
Ghule AE, Kandhare AD, Jadhav SS, Zanwar AA, Bodhankar SL (2015) Omega-3-fatty acid adds to the protective effect of flax lignan concentrate in pressure overload-induced myocardial hypertrophy in rats via modulation of oxidative stress and apoptosis. Int Immunopharmacol 28:751–763
Oz E, Ilhan MN (2006) Effects of melatonin in reducing the toxic effects of doxorubicin. Mol Cell Biochem 286:11–15
Hla T, Neilson K (1992) Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci USA 89:7384–7388
Ibrahim MA, Morsy MA, Hafez HM, Gomaa WM, Abdelrahman AM (2012) Effect of selective and non-selective cyclooxygenase inhibitors on doxorubicin-induced cardiotoxicity and nephrotoxicity in rats. Toxicol Mech Methods 22:424–431
Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB et al (2000) The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342:1946–1952
Yi C, Zhang Y, Yu Z, Xiao Y, Wang J, Qiu H et al (2014) Melatonin enhances the anti-tumor effect of fisetin by inhibiting COX-2/iNOS and NF-kappaB/p300 signaling pathways. PLoS ONE 9:e99943
O’Brien PJ, Smith DE, Knechtel TJ, Marchak MA, Pruimboom-Brees I, Brees DJ et al (2006) Cardiac troponin I is a sensitive, specific biomarker of cardiac injury in laboratory animals. Lab Anim 40:153–171
Henri C, Heinonen T, Tardif JC (2016) The Role of biomarkers in decreasing risk of cardiac toxicity after cancer therapy. Biomark Cancer 8:39–45
Kavsak PA, MacRae AR, Lustig V, Bhargava R, Vandersluis R, Palomaki GE et al (2006) The impact of the ESC/ACC redefinition of myocardial infarction and new sensitive troponin assays on the frequency of acute myocardial infarction. Am Heart J 152:118–125
Dudka J, Gieroba R, Korga A, Burdan F, Matysiak W, Jodlowska-Jedrych B et al (2012) Different effects of resveratrol on dose-related Doxorubicin-induced heart and liver toxicity. Evid Based Complement Alternat Med 2012:606183
Sun Z, Yan B, Yu WY, Yao X, Ma X, Sheng G et al (2016) Vitexin attenuates acute doxorubicin cardiotoxicity in rats via the suppression of oxidative stress, inflammation and apoptosis and the activation of FOXO3a. Exp Ther Med 12:1879–1884
Guo RM, Xu WM, Lin JC, Mo LQ, Hua XX, Chen PX et al (2013) Activation of the p38 MAPK/NF-kappaB pathway contributes to doxorubicin-induced inflammation and cytotoxicity in H9c2 cardiac cells. Mol Med Rep 8:603–608
Abdel-Daim MM, Kilany OE, Khalifa HA, Ahmed AAM (2017) Allicin ameliorates doxorubicin-induced cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis. Cancer Chemother Pharmacol 80:745–753
Shah KS, Yang EH, Maisel AS, Fonarow GC (2017) The role of biomarkers in detection of cardio-toxicity. Curr Oncol Rep 19:42
El-Shitany NA, El-Desoky K (2016) Protective effects of carvedilol and vitamin C against azithromycin-induced cardiotoxicity in rats via decreasing ROS, IL1-β, and TNF-α production and inhibiting NF-κB and caspase-3 expression. Oxid Med Cell Longev. 2016:1874762
Davitashvili DT, Museridze DP, Svanidze IK, Gegenava LG, Sanikidze TV (2009) [Investigation of oxidative stress-induced alterations in the rat brain cortical cellular culture and their correction with vitamines E and C]. Georgian Med News. 177:73–77
Saad SY, Najjar TA, Arafah MM (2006) Cardioprotective effects of subcutaneous ebselen against daunorubicin-induced cardiomyopathy in rats. Basic Clin Pharmacol Toxicol 99:412–417
Tebbi CK, London WB, Friedman D, Villaluna D, De Alarcon PA, Constine LS et al (2007) Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin’s disease. J Clin Oncol 25:493–500
Zhang J, Cui X, Yan Y, Li M, Yang Y, Wang J et al (2016) Research progress of cardioprotective agents for prevention of anthracycline cardiotoxicity. Am J Transl Res 8:2862–2875
Iarussi D, Auricchio U, Agretto A, Murano A, Giuliano M, Casale F et al (1994) Protective effect of coenzyme Q10 on anthracyclines cardiotoxicity: control study in children with acute lymphoblastic leukemia and non-Hodgkin lymphoma. Mol Aspects Med 15:s207–212
Wagdi P, Rouvinez G, Fluri M, Aeschbacher B, Thoni A, Schefer H et al (1995) [Cardioprotection in chemo- and radiotherapy for malignant diseases–an echocardiographic pilot study]. Praxis 84:1220–1223
Acknowledgements
The authors would like to acknowledge Dr. S. S. Kadam, Chancellor, and Dr. K. R. Mahadik, Principal, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Pune for providing necessary facilities to carry out the study.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Ethical approval
The experimental protocol was approved by the Institutional Animal Ethics Committee (IAEC) of Poona College of Pharmacy, Pune and performed in accordance with the guidelines of Committee for Control and Supervision of Experimentation on Animals, Government of India on animal experimentation.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Ma, T., Kandhare, A.D., Mukherjee-Kandhare, A.A. et al. Fisetin, a plant flavonoid ameliorates doxorubicin-induced cardiotoxicity in experimental rats: the decisive role of caspase-3, COX-II, cTn-I, iNOs and TNF-α. Mol Biol Rep 46, 105–118 (2019). https://doi.org/10.1007/s11033-018-4450-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-018-4450-y