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 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 with up-regulating 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 mono-therapy 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.
Molecular cancer therapeutics. 2016 Jul 12 [Epub ahead of print]
Seijiro Toriyama, Mano Horinaka, Shusuke Yasuda, Tomoyuki Taniguchi, Yuichi Aono, Toshiya Takamura, Yukako Morioka, Tsuneharu Miki, Osamu Ukimura, Toshiyuki Sakai
Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine., Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine ., Department of Molecular-targeting Cancer Prevention, Kyoto Prefectural University of Medicine., Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine., Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine., Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine., Department of Urology, Kyoto Prefectural University of Medicine., Department of Urology, Kyoto Prefectural University of Medicine., Department of Urology, Kyoto Prefectural University of Medicine., Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine.