FGFR inhibitor BGJ398 and HDAC inhibitor OBP-801 synergistically inhibit cell growth and induce apoptosis in bladder cancer cells

Takamura,Toshiya; Horinaka,Mano; Yasuda,Shusuke; Toriyama,Seijiro; Aono,Yuichi; Sowa,Yoshihiro; Miki,Tsuneharu; Ukimura,Osamu; Sakai,Toshiyuki

doi:10.3892/or.2017.6127

FGFR inhibitor BGJ398 and HDAC inhibitor OBP-801 synergistically inhibit cell growth and induce apoptosis in bladder cancer cells

Authors:
- Toshiya Takamura
- Mano Horinaka
- Shusuke Yasuda
- Seijiro Toriyama
- Yuichi Aono
- Yoshihiro Sowa
- Tsuneharu Miki
- Osamu Ukimura
- Toshiyuki Sakai
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Affiliations: Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan, Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan
Published online on: December 1, 2017 https://doi.org/10.3892/or.2017.6127
Pages: 627-632

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Abstract

In advanced bladder cancer, cisplatin-based chemotherapy has been the standard treatment for many years, but there are many problems in terms of side-effects. Recently, a number of clinical trials using molecular-targeted agents have been conducted, and new therapies are expected that could replace conventional cytotoxic chemotherapy. We herein report that concurrent treatment with fibroblast growth factor receptor (FGFR) inhibitor BGJ398 and the novel histone deacetylase (HDAC) inhibitor OBP-801/YM753/spiruchostatin A synergistically inhibited cell growth and markedly induced apoptosis in high-grade bladder cancer cells. This combination activated caspase-3, -8 and -9, and the pan-caspase inhibitor zVAD-fmk significantly reduced the apoptotic response to the combined treatment. The combination upregulated the expression of Bim, one of the pro-apoptotic molecules. In the present study, Bim siRNA efficiently reduced apoptosis induced by the co-treatment of BGJ398 and OBP-801. Therefore, the apoptosis induced by the combination was shown to be at least partially dependent on Bim. Taken together, these results suggest that the combination of BGJ398 and OBP-801 is a novel high potential therapeutic strategy for muscle-invasive bladder cancer.

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