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Cardiovascular Toxicology

, Volume 16, Issue 1, pp 46–53 | Cite as

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

  • Guozhen Cui
  • Huanxian Chen
  • Wei Cui
  • Xiaogang Guo
  • Jiansong Fang
  • Ailin Liu
  • Yonglong Chen
  • Simon Ming Yuen Lee
Article

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.

Keywords

Sunitinib Cardiotoxicity FGF2 Zebrafish PLC-γ/c-Raf/CREB 

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

Notes

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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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Guozhen Cui
    • 1
  • Huanxian Chen
    • 1
  • Wei Cui
    • 2
  • Xiaogang Guo
    • 3
  • Jiansong Fang
    • 4
  • Ailin Liu
    • 4
  • Yonglong Chen
    • 3
  • Simon Ming Yuen Lee
    • 1
  1. 1.State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical SciencesUniversity of MacauMacaoChina
  2. 2.School of MedicineNingbo UniversityNingboChina
  3. 3.Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhouChina
  4. 4.Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

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