Advertisement

Molecular Biology Reports

, Volume 46, Issue 1, pp 105–118 | Cite as

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

  • Tao Ma
  • Amit D. Kandhare
  • Anwesha A. Mukherjee-Kandhare
  • Subhash L. BodhankarEmail author
Original Article

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

Keywords

Cardiotoxic Caspase-3 COX-II cTn-I Doxorubicin Fisetin 

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

Notes

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.

Compliance with ethical standards

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.

Supplementary material

11033_2018_4450_MOESM1_ESM.docx (12 kb)
Supplementary material 1 (DOCX 12 KB)

References

  1. 1.
    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 29:3451–3460CrossRefPubMedGoogle Scholar
  2. 2.
    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 2011:390238CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    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 293:44–52CrossRefPubMedGoogle Scholar
  4. 4.
    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 12:233–240CrossRefPubMedGoogle Scholar
  5. 5.
    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 52:1213–1225CrossRefPubMedGoogle Scholar
  6. 6.
    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 82:773–783CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    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 7:36–39PubMedPubMedCentralGoogle Scholar
  8. 8.
    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 3:25–29CrossRefGoogle Scholar
  9. 9.
    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 2:31–44Google Scholar
  10. 10.
    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
  11. 11.
    van Acker F (2001) New synthetic flavonoids as potent protectors against doxorubicin-induced cardiotoxicity. Free Radic Biol Med 31:31–37CrossRefPubMedGoogle Scholar
  12. 12.
    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 5:236–243CrossRefGoogle Scholar
  13. 13.
    Raygude KS, Kandhare AD, Ghosh P, Bodhankar SL (2012) Anticonvulsant effect of fisetin by modulation of endogenous biomarkers. Biomed Prev Nutr 2:215–222CrossRefGoogle Scholar
  14. 14.
    Prasath GS, Subramanian SP (2014) Antihyperlipidemic effect of fisetin, a bioflavonoid of strawberries, studied in streptozotocin-induced diabetic rats. J Biochem Mol Toxicol 28:442–449CrossRefPubMedGoogle Scholar
  15. 15.
    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 42:1673–1681CrossRefPubMedGoogle Scholar
  16. 16.
    Kim JH, Kim MY, Kim JH, Cho JY (2015) Fisetin Suppresses Macrophage-Mediated Inflammatory Responses by Blockade of Src and Syk. Biomol Ther 23:414–420CrossRefGoogle Scholar
  17. 17.
    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. 2018:9173436CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    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 2015:424813CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    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 27:603–622CrossRefPubMedGoogle Scholar
  20. 20.
    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 37:482–493CrossRefPubMedGoogle Scholar
  21. 21.
    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 219:101–112CrossRefPubMedGoogle Scholar
  22. 22.
    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 52:814–828CrossRefPubMedGoogle Scholar
  23. 23.
    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 2:85–97CrossRefGoogle Scholar
  24. 24.
    Chen JY, Hu RY, Chou HC (2013) Quercetin-induced cardioprotection against doxorubicin cytotoxicity. J Biomed Sci 20:95CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    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 32:31–38CrossRefPubMedGoogle Scholar
  26. 26.
    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 10:391–399CrossRefPubMedGoogle Scholar
  27. 27.
    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 13:699–709CrossRefPubMedGoogle Scholar
  28. 28.
    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 12:63CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    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 6:230–241CrossRefPubMedGoogle Scholar
  30. 30.
    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 9:360–364CrossRefPubMedGoogle Scholar
  31. 31.
    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:e105070CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229CrossRefPubMedGoogle Scholar
  33. 33.
    Zhou S, Palmeira CM, Wallace KB (2001) Doxorubicin-induced persistent oxidative stress to cardiac myocytes. Toxicol Lett 121:151–157CrossRefPubMedGoogle Scholar
  34. 34.
    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 13:116–124CrossRefPubMedGoogle Scholar
  35. 35.
    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 53:571–581CrossRefPubMedGoogle Scholar
  36. 36.
    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 28:751–763CrossRefPubMedGoogle Scholar
  37. 37.
    Oz E, Ilhan MN (2006) Effects of melatonin in reducing the toxic effects of doxorubicin. Mol Cell Biochem 286:11–15CrossRefPubMedGoogle Scholar
  38. 38.
    Hla T, Neilson K (1992) Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci USA 89:7384–7388CrossRefPubMedGoogle Scholar
  39. 39.
    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 22:424–431CrossRefPubMedGoogle Scholar
  40. 40.
    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 342:1946–1952CrossRefPubMedGoogle Scholar
  41. 41.
    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:e99943CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    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 40:153–171CrossRefPubMedGoogle Scholar
  43. 43.
    Henri C, Heinonen T, Tardif JC (2016) The Role of biomarkers in decreasing risk of cardiac toxicity after cancer therapy. Biomark Cancer 8:39–45PubMedPubMedCentralGoogle Scholar
  44. 44.
    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 152:118–125CrossRefPubMedGoogle Scholar
  45. 45.
    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 2012:606183CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    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 12:1879–1884CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    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 8:603–608CrossRefPubMedGoogle Scholar
  48. 48.
    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 80:745–753CrossRefPubMedGoogle Scholar
  49. 49.
    Shah KS, Yang EH, Maisel AS, Fonarow GC (2017) The role of biomarkers in detection of cardio-toxicity. Curr Oncol Rep 19:42CrossRefPubMedGoogle Scholar
  50. 50.
    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. 2016:1874762CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    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. 177:73–77Google Scholar
  52. 52.
    Saad SY, Najjar TA, Arafah MM (2006) Cardioprotective effects of subcutaneous ebselen against daunorubicin-induced cardiomyopathy in rats. Basic Clin Pharmacol Toxicol 99:412–417CrossRefPubMedGoogle Scholar
  53. 53.
    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 25:493–500CrossRefPubMedGoogle Scholar
  54. 54.
    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 8:2862–2875PubMedPubMedCentralGoogle Scholar
  55. 55.
    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:s207–212CrossRefPubMedGoogle Scholar
  56. 56.
    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 84:1220–1223PubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Department of CardiologyThe First People’s Hospital of Yunnan ProvinceKunmingChina
  2. 2.Department of Pharmacology, Poona College of PharmacyBharati Vidyapeeth Deemed UniversityPuneIndia

Personalised recommendations