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FGF2 Prevents Sunitinib-Induced Cardiotoxicity in Zebrafish and Cardiomyoblast H9c2 Cells

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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.

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Abbreviations

BA:

Bulbus arteriosus

CREB:

cAMP response element-binding protein

FGF2:

Fibroblast growth factor 2

Hpf:

Hours post-fertilization

LDH:

Lactate dehydrogenase

PLC:

Phospholipase C

SV:

Sinus venosus

TKI:

Tyrosine kinase inhibitor

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Acknowledgments

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.

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    Authors and Affiliations

    1. State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China

      Guozhen Cui, Huanxian Chen & Simon Ming Yuen Lee

    2. School of Medicine, Ningbo University, Ningbo, China

      Wei Cui

    3. 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

      Xiaogang Guo & Yonglong Chen

    4. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

      Jiansong Fang & Ailin Liu

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    1. Guozhen Cui
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    Correspondence to Simon Ming Yuen Lee.

    Additional information

    Guozhen Cui and Huanxian Chen have contributed equally to this work.

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    Cui, G., Chen, H., Cui, W. et al. FGF2 Prevents Sunitinib-Induced Cardiotoxicity in Zebrafish and Cardiomyoblast H9c2 Cells. Cardiovasc Toxicol 16, 46–53 (2016). https://doi.org/10.1007/s12012-015-9315-1

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