Toriyama Seijiro, Horinaka Mano, Yasuda Shusuke, Taniguchi Tomoyuki, Aono Yuichi, Takamura Toshiya, Morioka Yukako, Miki Tsuneharu, Ukimura Osamu, Sakai Toshiyuki
Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan. Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Mol Cancer Ther. 2016 Sep;15(9):2066-75. doi: 10.1158/1535-7163.MCT-16-0010. Epub 2016 Jul 12.
The prognosis of muscle-invasive bladder cancer with metastasis is poor. There have been no therapeutic improvements for many years, and an innovative therapy for muscle-invasive bladder cancer has been awaited to replace the conventional cytotoxic chemotherapy. Here, we show a candidate method for the treatment of bladder cancer. The combined treatment with a novel histone deacetylase (HDAC) inhibitor, OBP-801, and celecoxib synergistically inhibited cell growth and markedly induced apoptosis through the caspase-dependent pathway in high-grade bladder cancer cells. Furthermore, the combined treatment induced expression of death receptor 5 (DR5). We identified that knockdown of DR5 by small interfering RNA (siRNA) significantly suppressed apoptosis by the combined treatment. Therefore, we conjectured that the apoptosis induced by OBP-801 and celecoxib is at least partially dependent on DR5. However, it was interesting that the combined treatment drastically suppressed expression of DR5 ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). These data suggest that there is no involvement of TRAIL in the induction of apoptosis by the combination, regardless of the dependence of DR5. Moreover, xenograft studies using human bladder cancer cells showed that the combined therapy suppressed tumor growth by upregulating expressions of DR5 and Bim. The inhibition of tumor growth was significantly more potent than that of each agent alone, without significant weight loss. This combination therapy provided a greater benefit than monotherapy in vitro and in vivo These data show that the combination therapy with OBP-801 and celecoxib is a potential novel therapeutic strategy for patients with muscle-invasive bladder cancer. Mol Cancer Ther; 15(9); 2066-75. ©2016 AACR.
伴有转移的肌层浸润性膀胱癌预后较差。多年来一直没有治疗上的进展，人们期待有创新疗法来替代传统的细胞毒性化疗，用于治疗肌层浸润性膀胱癌。在此，我们展示了一种治疗膀胱癌的候选方法。新型组蛋白去乙酰化酶（HDAC）抑制剂OBP-801与塞来昔布联合治疗可协同抑制细胞生长，并通过半胱天冬酶依赖性途径在高级别膀胱癌细胞中显著诱导细胞凋亡。此外，联合治疗可诱导死亡受体5（DR5）的表达。我们发现，通过小干扰RNA（siRNA）敲低DR5可显著抑制联合治疗诱导的细胞凋亡。因此，我们推测OBP-801和塞来昔布诱导的细胞凋亡至少部分依赖于DR5。然而，有趣的是，联合治疗显著抑制了DR5配体肿瘤坏死因子相关凋亡诱导配体（TRAIL）的表达。这些数据表明，无论是否依赖DR5，联合治疗诱导的细胞凋亡均与TRAIL无关。此外，使用人膀胱癌细胞的异种移植研究表明，联合治疗通过上调DR5和Bim的表达来抑制肿瘤生长。抑制肿瘤生长的效果明显强于单一药物治疗，且无明显体重减轻。这种联合治疗在体外和体内均比单一疗法更具优势。这些数据表明，OBP-801与塞来昔布联合治疗是肌层浸润性膀胱癌患者潜在的新型治疗策略。《分子癌症治疗》；15(9)；2066 - 2075。©2016美国癌症研究协会。
