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


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


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



Alanine transaminase


Alkaline phosphatase


Atrial natriuretic peptide


Aspartate aminotransferase


Brain natriuretic peptide


Blood pressure per minute


Cardiac troponin I


Creatine kinase-MB




Deoxyribonucleic acid


Diastolic blood pressure


Inducible nitric oxide

IL 1β

Interleukin 1-β


Lactate dehydrogenase


Left ventricular end-diastolic pressure


Left ventricular end-systolic pressure


Mean arterial blood pressure




Nitric oxide


Reactive oxygen species


Reduced glutathione


Reverse transcription-polymerase chain reaction


Ribonucleic acid


Superoxide dismutase


Systolic blood pressure


Tumor necrosis factor-α



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)


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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

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