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Published on: June 7, 2018
FGF2 Prevents Sunitinib-Induced Cardiotoxicity in Zebrafish and Cardiomyoblast H9c2 Cells
Guozhen Cui1, Huanxian Chen1, Wei Cui2
1State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
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.
Insights
Fibroblast growth factor 2 (FGF2) protects against sunitinib cardiotoxicity by targeting FGF receptor 1. This finding offers potential for developing safer sunitinib derivatives for cancer treatment.
Area of Science:
- Cardiovascular Pharmacology
- Oncology
- Molecular Biology
Background:
- Sunitinib is a vital treatment for metastatic renal cell carcinoma and gastrointestinal stromal tumors.
- Sunitinib's clinical utility is hampered by cardiotoxic effects like heart failure and hypertension.
- The specific molecular targets mediating sunitinib-induced cardiotoxicity remain unclear.
Purpose of the Study:
- To investigate the role of fibroblast growth factor 2 (FGF2) in sunitinib-induced cardiotoxicity.
- To explore the potential of FGF2 as a protective agent against sunitinib cardiotoxicity.
- To elucidate the molecular mechanisms underlying FGF2's protective effects.
Main Methods:
- Zebrafish embryos injected with fibroblast growth factor 2 (FGF2) mRNA were used to study sunitinib cardiotoxicity in vivo.
- H9c2 cardiomyoblast cells were treated with FGF2 to assess protection against sunitinib in vitro.
- Molecular docking simulations were performed to analyze interactions between sunitinib and FGF receptor 1 (FGFR1).
- Antitumor activity of sunitinib was evaluated in renal cell carcinoma cell lines (Caki-1 and OS-RC-2) with and without FGF2 intervention.
Main Results:
- FGF2 administration protected zebrafish embryos from sunitinib-induced cardiotoxicity.
- FGF2 significantly mitigated sunitinib cardiotoxicity in H9c2 cells, potentially through the PLC-γ/c-Raf/CREB pathway.
- FGF2 did not diminish the antitumor efficacy of sunitinib against renal cell carcinoma cells.
- Molecular docking indicated direct interaction between sunitinib and the tyrosine kinase domain of FGFR1.
Conclusions:
- FGF2 plays a critical role in mitigating sunitinib-induced cardiotoxicity, both in vitro and in vivo.
- FGF2 inhibition is implicated in the cardiotoxic effects of sunitinib.
- These findings suggest FGF2 as a potential therapeutic target to reduce sunitinib cardiotoxicity and inform the design of safer sunitinib analogs.
