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Protective Effect of RIVA Against Sunitinib-Induced Cardiotoxicity by Inhibiting Oxidative Stress-Mediated Inflammation: Probable Role of TGF-β and Smad Signaling

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Abstract

Sunitinib (SUN) is an oral tyrosine kinase inhibitor approved in 2006 as a first-line treatment for metastatic renal cell cancer. However, weak selectivity to kinase receptors and cardiotoxicity have limited the use of sunitinib. Rivaroxaban (RIVA) is a Factor Xa inhibitor with cardioprotective action. It inhibits atherosclerosis and numerous inflammatory cascades. The present study was designed to investigate the cardioprotective effects of RIVA in sunitinib-induced cardiotoxicity. Thirty male Wistar rats were divided into five groups. Group 1 was the normal control (control). Group 2 was administered i.p. SUN 25 mg kg−1 thrice weekly for 3 weeks. Groups 3 and 4 received the same treatment as Group 2 followed by the administration of RIVA 5 mg kg−1 day−1 and 10 mg kg−1 day−1, respectively, for 3 weeks. Group 5 received only 10 mg kg−1 day−1 RIVA for 3 weeks. Serum levels of Ca2+, Mg2+, Fe3+/Fe2+, lipid profiles, and cardiac enzymes were measured. Cardiac tissues were isolated for the measurements of oxidant/antioxidant balance gene and protein expressions. Relative to the controls, the administration of SUN significantly altered serum levels of (Ca2+, Mg2+, Fe3+/Fe2+, lipid profiles, and cardiac enzymes), intracellular antioxidant enzymes, and the expression levels of the genes encoding certain proteins. RIVA treatment significantly restored these parameters to near-normal levels. RIVA treatment significantly mitigated SUN-induced cardiac injuries by restoring antioxidant enzyme levels and attenuating the proinflammatory cascades resulting from SUN-induced cardiac injuries.

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Acknowledgements

The present study was funded by the Deanship of Scientific Research, King Saud University through the research group project (Research Group No: RG-1439-019). The authors acknowledge the Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University for its facilities.

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  1. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia

    Faisal Imam, Naif Obaid Al-Harbi, Mohammad Rashid Khan, Wajhul Qamar, Metab Alharbi, Ali A. Alshamrani, Hussain N. Alhamami & Nasser Bader Alsaleh

  2. Central Laboratory; Research Center, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia

    Wajhul Qamar

  3. Department of Pharmacology, College of Pharmacy, Jouf University, Sakakah, 72341, Saudi Arabia

    Khalid Saad Alharbi

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  1. Faisal Imam
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Imam, F., Al-Harbi, N.O., Khan, M.R. et al. Protective Effect of RIVA Against Sunitinib-Induced Cardiotoxicity by Inhibiting Oxidative Stress-Mediated Inflammation: Probable Role of TGF-β and Smad Signaling. Cardiovasc Toxicol 20, 281–290 (2020). https://doi.org/10.1007/s12012-019-09551-8

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