Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Oncol Rep. 2018 Feb;39(2):627-632. doi: 10.3892/or.2017.6127. Epub 2017 Dec 1.
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.
在晚期膀胱癌中，顺铂为基础的化疗多年来一直是标准治疗方法，但存在许多副作用问题。最近，已经进行了许多使用分子靶向药物的临床试验，预计会有新的治疗方法可以替代传统的细胞毒性化疗。我们在此报告，成纤维细胞生长因子受体（FGFR）抑制剂 BGJ398 与新型组蛋白去乙酰化酶（HDAC）抑制剂 OBP-801/YM753/螺旋他汀 A 联合治疗可协同抑制高级别膀胱癌细胞的生长并显著诱导细胞凋亡。这种组合激活了 caspase-3、-8 和 -9，泛 caspase 抑制剂 zVAD-fmk 显著降低了联合治疗的凋亡反应。该组合上调了促凋亡分子 Bim 的表达。在本研究中，Bim siRNA 有效减少了 BGJ398 和 OBP-801 联合治疗诱导的细胞凋亡。因此，组合诱导的细胞凋亡至少部分依赖于 Bim。总之，这些结果表明，BGJ398 和 OBP-801 的联合治疗是肌层浸润性膀胱癌的一种新的潜在的治疗策略。
