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

  • Faisal ImamEmail author
  • Naif Obaid Al-Harbi
  • Mohammad Rashid Khan
  • Wajhul Qamar
  • Metab Alharbi
  • Ali A. Alshamrani
  • Hussain N. Alhamami
  • Nasser Bader Alsaleh
  • Khalid Saad Alharbi


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.


Cardiotoxicity Gene expressions ELISA Rivaroxaban Sunitinib Antioxidant 



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.

Compliance with Ethical Standards

Conflict of interest

The authors declare that there is no conflict of interest.


  1. 1.
    Le Tourneau, C., Raymond, E., & Faivre, S. (2007). Sunitinib: A novel tyrosine kinase inhibitor. A brief review of its therapeutic potential in the treatment of renal carcinoma and gastrointestinal stromal tumors (GIST). Therapeutics and Clinical Risk Management, 3, 341.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Awazu, Y., Mizutani, A., Nagase, Y., Iwata, H., Oguro, Y., Miki, H., et al. (2012). A novel pyrrolo [3,2-d] pyrimidine derivative, as a vascular endothelial growth factor receptor and platelet-derived growth factor receptor tyrosine kinase inhibitor, shows potent antitumor activity by suppression of tumor angiogenesis. Cancer Science, 103(5), 939–944.PubMedCrossRefGoogle Scholar
  3. 3.
    Force, T., Krause, D. S., & Van Etten, R. A. (2007). Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nature Reviews Cancer, 7, 332–344.PubMedCrossRefGoogle Scholar
  4. 4.
    Chu, T. F., Rupnick, M. A., Kerkela, R., Dallabrida, S. M., Zurakowski, D., Nguyen, L., et al. (2007). Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. The Lancet, 370, 2011–2019.CrossRefGoogle Scholar
  5. 5.
    Kerkela, R., Grazette, L., Yacobi, R., Iliescu, C., Patten, R., Beahm, C., et al. (2006). Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature Medicine, 12, 908–916.PubMedCrossRefGoogle Scholar
  6. 6.
    Khakoo, A. Y., Kassiotis, C. M., Tannir, N., Plana, J. C., Halushka, M., Bickford, C., et al. (2008). Heart failure associated with sunitinib malate. Cancer, 112, 2500–2508. Scholar
  7. 7.
    Vimalesvaran, K., Dockrill, S. J., & Gorog, D. A. (2018). Role of rivaroxaban in the management of atrial fibrillation: Insights from clinical practice. Vascular Health and Risk Management, 14, 13–21.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Sharma, A., Garg, A., Borer, J. S., Krishnamoorthy, P., Garg, J., Lavie, C. J., et al. (2014). Role of oral factor Xa inhibitors after acute coronary syndrome. Cardiology, 129(4), 224–232.PubMedCrossRefGoogle Scholar
  9. 9.
    Hara, T., Fukuda, D., Tanaka, K., Higashikuni, Y., Hirata, Y., Nishimoto, S., et al. (2015). Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice. Atherosclerosis, 242(2), 639–646.PubMedCrossRefGoogle Scholar
  10. 10.
    Sparkenbaugh, E. M., Chantrathammachart, P., Mickelson, J., van Ryn, J., Hebbel, R. P., Monroe, D. M., et al. (2014). Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease. Blood, 123(11), 1747–1756.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Bukowska, A., Zacharias, I., Weinert, S., Skopp, K., Hartmann, C., Huth, C., et al. (2013). Coagulation factor Xa induces an inflammatory signalling by activation of protease activated receptors in human atrial tissue. European Journal of Pharmacology, 718(13), 114–123.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Ishibashi, Y., Matsui, T., Ueda, S., Fukami, K., & Yamagishi, S. (2014). Advanced glycation end products potentiate citrated plasma evoked oxidative and inflammatory reactions in endothelial cells by upregulating protease activated receptor 1 expression. Cardiovascular Diabetology, 13, 60.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Iba, T., Aihara, K., Yamada, A., Nagayama, M., Tabe, Y., & Ohsaka, A. (2014). Rivaroxaban attenuates leukocyte adhesion in the microvasculature and thrombus formation in an experimental mouse model of type 2 diabetes Mellitus. Thrombosis Research, 133(2), 276–280.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Dammacco, F., Vacca, A., Procaccio, P., Ria, R., Marech, I., & Racanelli, V. (2013). Cancer related coagulopathy (Trousseau’s syndrome): Review of the literature and experience of a single center of internal medicine. International Journal of Clinical and Experimental Medicine, 13(2), 85–97.CrossRefGoogle Scholar
  15. 15.
    Blasi, E., Heyen, J., Patyna, S., Hemkens, M., Ramirez, D., John-Baptiste, A., et al. (2012). Sunitinib, a receptor tyrosine kinase inhibitor, increases blood pressure in rats without associated changes in cardiac structure and function. Cardiovascular Therapeutics, 30(5), 287–294.PubMedCrossRefGoogle Scholar
  16. 16.
    Yang, Y., Li, N., Chen, T., Zhang, C., Liu, L., Qi, Y., et al. (2019). Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway. Pharmaceutical Biology, 57(1), 625–631.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Kerkela, R., Woulfe, K. C., Durand, J. B., Vagnozzi, R., Kramer, D., Chu, T. F., et al. (2009). Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase. Clinical and Translational Science, 2(1), 15–25.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Fujiwara, Y., Ando, H., Ushijima, K., Horiguchi, M., Yamashita, C., & Fujimura, A. (2017). Dosing-time-dependent effect of rivaroxaban on coagulation activity in rats. Journal of Pharmacological Sciences, 134(4), 234–238.PubMedCrossRefGoogle Scholar
  19. 19.
    Perzborn, Elisabeth, Hirth-Dietrich, Claudia, Fischer, Elke, Groth, Martin, Hartmann, Elke, & Sperlich-Wulf, Kerstin. (2007). Rivaroxaban has protective effects in a model of disseminated intravascular coagulation (DIC) in rats. Blood, 110, 935.Google Scholar
  20. 20.
    Imam, F., Al-Harbi, N. O., Al-Harbi, M. M., et al. (2015). Diosmin downregulates the expression of T cell receptors, pro-inflammatory cytokines and NF-kB activation against LPS-induced acute lung injury in mice. Pharmacological Research, 102, 1–11.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Imam, F., Al-Harbi, N. O., Al-Harbia, M. M., Korashy, H. M., Ansari, M. A., Sayed-Ahmed, M. M., et al. (2017). Rutin attenuates carfilzomib-induced cardiotoxicity through inhibition of NF-kappaB, hypertrophic gene expression and oxidative stress. Cardiovascular Toxicology, 17(1), 58–66.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Sedlak, J., & Lindsay, R. H. (1968). Estimation of total, protein bound and non-protein bound sulfhydryl groups in tissue with Ellman’s reagent. Analytical Biochemistry, 25, 192–205.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Carlberg, I., & Mannervik, B. (1985). Glutathione reductase. Methods in Enzymology, 113, 484–490.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Al-Harbi, N. O. (2016). Carfilzomib-induced cardiotoxicity mitigated by dexrazoxane through inhibition of hypertrophic gene expression and oxidative stress in rats. Toxicology Mechanisms and Methods, 26(3), 189–195.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Ahmad, S. F., Zoheir, K. M., Ansari, M. A., et al. (2015). Histamine 4 receptor promotes expression of costimulatory B7.1/B7.2 molecules, CD28 signaling and cytokine production in stress induced immune responses. Journal of Neuroimmunology, 15(289), 30–42.CrossRefGoogle Scholar
  26. 26.
    Barakat, M. M., El-Kadi, A. O., & du Souich, P. (2001). L-NAME prevents in vivo the inactivation but not the down-regulation of hepatic cytochrome P450 caused by an acute inflammatory reaction. Life Sciences, 69, 1559–1571.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Lowry, O. H., Rosebrough, N. J., Farr, A. L., & Randall, R. J. (1951). Protein with the Folin phenol reagent. Journal of Biological Chemistry, 193(1), 265–275.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Abrams, T. J., Lee, J. B., Murray, L. J., Pryer, N. K., & Cherrington, J. M. (2003). SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Molecular Cancer Therapeutics, 2, 471–478.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Mendel, D. B., Laird, A. D., Xin, X., et al. (2003). In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clinical Cancer Research, 9, 327–337.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Le Tourneau, Christophe, Raymond, Eric, & Faivre, Sandrine. (2007). Sunitinib: a novel tyrosine kinase inhibitor: A brief review of its therapeutic potential in the treatment of renal carcinoma and gastrointestinal stromal tumors (GIST). Therapeutics and Clinical Risk Management, 3(2), 341–348.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Sandhu, Hardip, Cooper, Samantha, Hussain, Afthab, Mee, Christopher, & Maddock, Helen. (2017). Attenuation of Sunitinib-induced cardiotoxicity through the A3 adenosine receptor activation. European Journal of Pharmacology, 814, 95–105.PubMedCrossRefGoogle Scholar
  32. 32.
    Uraizee, I., Cheng, S., & Moslehi, J. (2011). Reversible cardiomyopathy associated with sunitinib and sorafenib. New England Journal of Medicine, 365, 1649–1650.PubMedCrossRefGoogle Scholar
  33. 33.
    Mooney, L., Skinner, M., Coker, S., & Currie, S. (2015). Effects of acute and chronic sunitinib treatment on cardiac function and calcium/calmodulin-dependent protein kinase II. British Journal of Pharmacology, 172, 4342–4354.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Gorini, S., De Angelis, A., Berrino, L., Malara, N., Rosano, G., & Ferraro, E. (2018). Chemotherapeutic drugs and mitochondrial dysfunction: Focus on doxorubicin, trastuzumab, and sunitinib. Oxidative Medicine and Cellular Longevity. Scholar
  35. 35.
    Georgieva, E., Ivanova, D., Zhelev, Z., Bakalova, R., Gulubova, M., & Aoki, I. (2017). Mitochondrial dysfunction and redox imbalance as a diagnostic marker of “Free Radical Diseases”. Anticancer Research, 37(10), 5373–5381.PubMedGoogle Scholar
  36. 36.
    Sridharan, Vijayalakshmi, Thomas, Chanice J., Cao, Maohua, Melnyk, Stepan B., Pavliv, Oleksandra, Joseph, Jacob, et al. (2016). Effects of local irradiation combined with sunitinib on early remodeling, mitochondria, and oxidative stress in the rat heart. Radiotherapy and Oncology, 119(2), 259–264. Scholar
  37. 37.
    Ishibashi, Y., Matsui, T., Fukami, K., Ueda, S., Okuda, S., & Yamagishi, S. (2015). Rivaroxaban inhibits oxidative and inflammatory reactions in advanced glycation end product-exposed tubular cells by blocking thrombin/protease-activated receptor-2 system. Thrombosis Research, 135, 770–773.PubMedCrossRefGoogle Scholar
  38. 38.
    Balasubramaniyan, V., & Nalini, N. (2007). Effect of leptin on peroxidation and antioxidant defense in ethanol-supplemented Mus musculus heart. Fundamental & Clinical Pharmacology, 21, 245–253.CrossRefGoogle Scholar
  39. 39.
    Saravanan, R., & Pugalendi, V. (2006). Impact of ursolic acid on chronic ethanol-induced oxidative stress in the rat heart. Pharmacological Reports, 58, 41–47.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Subbaiah, G. V., Mallikarjuna, K., Shanmugam, B., Ravi, S., Taj, P. U., & Reddy, K. S. (2017). Ginger treatment ameliorates alcohol-induced myocardial damage by suppression of hyperlipidemia and cardiac biomarkers in rats. Pharmacognosy Magazine, 13(Suppl 1), S69–S75.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Huang, Q., Zhou, C., Chen, X., Dong, B., Chen, S., Zhang, N., et al. (2015). Prodrug AST-003 improves the therapeutic index of the multi-targeted tyrosine kinase inhibitor sunitinib. PLoS ONE, 10(10), e0141395.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Janet, K., Lighthouse, C., & Eric, M. (2016). Small. Transcriptional control of cardiac fibroblast plasticity. Journal of Molecular and Cellular Cardiology, 91, 52–60.CrossRefGoogle Scholar
  43. 43.
    Bujak, M., & Frangogiannis, N. G. (2007). The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovascular Research, 74(2), 184–195.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Creemers, E. E., & Pinto, Y. M. (2011). Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart. Cardiovascular Research, 89, 265–272.PubMedCrossRefGoogle Scholar
  45. 45.
    Massague, J., Seoane, J., & Wotton, D. (2008). Smad transcription factors. Genes & Development, 19(23), 2783–2810.CrossRefGoogle Scholar
  46. 46.
    Nakao, A., Afrakhte, M., Morén, A., Nakayama, T., Christian, J. L., Heuchel, R., et al. (1997). Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature, 389(6651), 631–635.PubMedCrossRefGoogle Scholar
  47. 47.
    Dobaczewski, M., Bujak, M., Li, N., Gonzalez-Quesada, C., Mendoza, L. H., Wang, X. F., et al. (2010). Smad3 signaling critically regulates fibroblast phenotype and function in healing myocardial infarction. Circulation Research, 107(3), 418–428.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Biernacka, A., Cavalera, M., Wang, J., Russo, I., Shinde, A., Kong, P., et al. (2015). Smad3 signaling promotes fibrosis while preserving cardiac and aortic geometry in obese diabetic mice. Circulation: Heart Failure, 8(4), 788–798.Google Scholar
  49. 49.
    Massagué, J. (1998). TGF-β signal transduction. Annual Review of Biochemistry, 67, 753–791.PubMedCrossRefGoogle Scholar
  50. 50.
    Yuan, S. M., & Jing, H. (2010). Cardiac pathologies in relation to Smad-dependent pathways. Interactive CardioVascular and Thoracic Surgery, 11, 455–460.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Barnette, D. N., Hulin, A., Ahmed, A. S., Colige, A. C., Azhar, M., & Lincoln, J. (2013). TGF-β-Smad and MAPK signaling mediate scleraxis and proteoglycan expression in heart valves. Journal of Molecular and Cellular Cardiology, 65, 137–146.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Rodríguez-Vita, J., Sánchez-López, E., Esteban, V., Rupérez, M., Egido, J., & Ruiz-Ortega, M. (2005). Angiotensin II activates the Smad pathway in vascular smooth muscle cells by a transforming growth factor-β–independent mechanism. Circulation, 111, 2509–2517.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Isono, M., Chen, S., Won Hong, S., Iglesias-de, Carmen, la Cruz, M., & Ziyadeh, F. N. (2002). Smad pathway is activated in the diabetic mouse kidney and Smad3 mediates TGF-β-induced fibronectin in mesangial cells. Biochemical and Biophysical Research Communications, 296, 1356–1365.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Chen, Y. G., Hata, A., Lo, R. S., Wotton, D., Shi, Y., Pavletich, N., et al. (1998). Determinants of specificity in TGF-β signal transduction. Genes & Development, 12, 2144–2152.CrossRefGoogle Scholar
  55. 55.
    Akhurst, R. J., & Hata, A. (2012). Targeting the TGF-β signalling pathway in disease. Nature Reviews Drug Discovery, 11, 790–811.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Bujak, M., & Frangogiannis, N. G. (2007). The role of TGF-β signaling in myocardial infarction and cardiac remodeling. Cardiovascular Research, 74, 184–195.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Derynck, R., & Zhang, Y. E. (2003). Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature, 425, 577–584.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Massagué, J., & Chen, Y. G. (2000). Controlling TGF-β signaling. Genes & Development, 14(6), 627–644.Google Scholar
  59. 59.
    Jumeau, C., Rupin, A., Chieng-Yane, P., Mougenot, N., Zahr, N., David-Dufilho, M., et al. (2016). Direct thrombin inhibitors prevent left atrial remodeling associated with heart failure in rats. JACC: Basic to Translational Science, 1(5), 328–339.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Korashy, H. M., Al-Suwayeh, H. A., Maayah, Z. H., Ansari, M. A., Ahmad, S. F., & Bakheet, S. A. (2015). Mitogen-activated protein kinases pathways mediate the sunitinib-induced hypertrophy in rat cardiomyocyte H9c2 cells. Cardiovascular Toxicology, 15(1), 41–51.PubMedCrossRefPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Faisal Imam
    • 1
    Email author
  • Naif Obaid Al-Harbi
    • 1
  • Mohammad Rashid Khan
    • 1
  • Wajhul Qamar
    • 1
    • 2
  • Metab Alharbi
    • 1
  • Ali A. Alshamrani
    • 1
  • Hussain N. Alhamami
    • 1
  • Nasser Bader Alsaleh
    • 1
  • Khalid Saad Alharbi
    • 3
  1. 1.Department of Pharmacology and Toxicology, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia
  2. 2.Central Laboratory; Research Center, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia
  3. 3.Department of Pharmacology, College of PharmacyJouf UniversitySakakahSaudi Arabia

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