FGF2 Prevents Sunitinib-Induced Cardiotoxicity in Zebrafish and Cardiomyoblast H9c2 Cells
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Sunitinib is used extensively in the treatment of metastatic renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. However, the undesirable cardiotoxic effects of sunitinib, such as congestive heart failure and hypertension, limit its use in the clinical setting. As multiple receptor tyrosine kinases are inhibited by sunitinib, it raises a question as to which target mediates sunitinib-induced cardiotoxicity. Here, we reported that the injection of fibroblast growth factor 2 (FGF2) mRNA into one- to two-cell stage embryos protected against sunitinib-induced cardiotoxicity in zebrafish. In addition, FGF2 significantly prevented sunitinib-induced cardiotoxicity in cardiomyoblast H9c2 cells, possibly via activating the PLC-γ/c-Raf/CREB pathway. Importantly, FGF2 did not compromise the antitumor activity of sunitinib in Caki-1 and OS-RC-2 renal cell carcinoma cells. Molecular docking simulations further revealed an interaction between the tyrosine kinase domain of FGF receptor 1 (FGFR1) and sunitinib. Taken together, our results clearly demonstrated that FGF2 inhibition plays an important role in sunitinib-induced cardiotoxicity both in vitro and in vivo. This study also provided a basis for further research on sunitinib-induced cardiotoxicity and may allow rational design of new sunitinib derivatives with fewer or weak cardiotoxic effects.
KeywordsSunitinib Cardiotoxicity FGF2 Zebrafish PLC-γ/c-Raf/CREB
cAMP response element-binding protein
Fibroblast growth factor 2
Tyrosine kinase inhibitor
This work was supported by grants from the Science and Technology Development Fund Macao SAR, China (Grant No. 014/2011/A1) and the National Natural Science Foundation of China (Grant No. 31301192).
Conflict of interest
The authors declare that there are no conflicts of interest.
- 6.Chan, J., & Mably, J. D. (2011). Dissection of Cardiovascular Development and Disease Pathways in Zebrafish. In K. T. Chang & K. T. Min (Eds.), Progress in molecular biology and translational science: animal models of human disease (Vol. 100, pp. 111–153). San Diego: Elsevier Academic Press Inc.CrossRefGoogle Scholar
- 15.Westerfield, M. (1995). The zebrafish book: A guide for the laboratory use of zebrafish (Danio rerio), 3rd Edition Eugene (pp. 267–272). OR: University of Oregon.Google Scholar
- 22.Marcolino, M. S., Ribeiro, A. L., Clementino, N. C. D., Nunes, M. D. P., Barbosa, M. M., Silva, M., et al. (2011). The use of imatinib mesylate has no adverse effects on the heart function. Results of a pilot study in patients with chronic myeloid leukemia. Leukemia Research, 35, 317–322.CrossRefPubMedGoogle Scholar
- 23.Jiang, Z. S., Jeyaraman, M., Wen, G. B., Fandrich, R. R., Dixon, I. M., Cattini, P. A., & Kardami, E. (2007). High- but not low-molecular weight FGF-2 causes cardiac hypertrophy in vivo; possible involvement of cardiotrophin-1. Journal of Molecular and Cellular Cardiology, 42, 222–233.CrossRefPubMedGoogle Scholar
- 25.Anestopoulos, I., Kavo, A., Tentes, I., Kortsaris, A., Panayiotidis, M., Lazou, A., & Pappa, A. (2013). Silibinin protects H9c2 cardiac cells from oxidative stress and inhibits phenylephrine-induced hypertrophy: potential mechanisms. Journal of Nutritional Biochemistry, 24, 586–594.CrossRefPubMedGoogle Scholar
- 27.House, S. L., Melhorn, S. J., Newman, G., Doetschman, T., & Schultz, J. E. (2007). The protein kinase C pathway mediates cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2. American Journal of Physiology-Heart and Circulatory Physiology, 293, H354–H365.CrossRefPubMedGoogle Scholar