title: FGF2 Prevents Sunitinib-Induced Cardiotoxicity in Zebrafish and Cardiomyoblast H9c2 Cells.
abstract: 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.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Guozhen
authors.initials: G
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Huanxian
authors.initials: H
authors.lastname: Chen
authors.affiliation: School of Medicine, Ningbo University, Ningbo, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.affiliation: Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Guo
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jiansong
authors.initials: J
authors.lastname: Fang
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Ailin
authors.initials: A
authors.lastname: Liu
authors.affiliation: Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Yonglong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China. simonlee@umac.mo.
authors.forename: Simon Ming Yuen
authors.initials: SM
authors.lastname: Lee
mesh_terms: D020533:Angiogenesis Inhibitors / Q000633:toxicity*; D000818:Animals; D066126:Cardiotoxicity / Q000517:prevention & control*; D002460:Cell Line; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000627:therapeutic use*; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D062105:Molecular Docking Simulation; D032446:Myoblasts / Q000187:drug effects*; D051966:Phospholipase C gamma / Q000187:drug effects / Q000378:metabolism; D011758:Pyrroles / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000187:drug effects / Q000378:metabolism; D000077210:Sunitinib; D015027:Zebrafish; D048490:raf Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D017362:Cyclic AMP Response Element-Binding Protein; D007211:Indoles; D011758:Pyrroles; D016222:Fibroblast Growth Factor 2; D051496:Receptor, Fibroblast Growth Factor, Type 1; D048490:raf Kinases; D051966:Phospholipase C gamma; D000077210:Sunitinib
keywords: Cardiotoxicity; FGF2; PLC-γ/c-Raf/CREB; Sunitinib; Zebrafish