Low-dose Hsp90 inhibitors tumor-selectively sensitize bladder cancer cells to chemoradiotherapy

• DOI: 10.4161/cc.10.24.18616
• Publication Date: 2012-01-11T17:55:11Z
• Authors: Soichiro Yoshida; Fumitaka Koga; Manabu Tatokoro; Satoru Kawakami; Yasuhisa Fujii; Jiro Kumagai; Len Neckers; Kazunori Kihara
• Keywords: Radiation-Sensitizing Agents; Dose-Response Relationship, Drug; Receptor, ErbB-2; Lactams, Macrocyclic; Immunoblotting; NF-kappa B; Fluorescent Antibody Technique; Apoptosis; Chemoradiotherapy; In Vitro Techniques; Statistics, Nonparametric; 3. Good health; Mice; 03 medical and health sciences; 0302 clinical medicine; Urinary Bladder Neoplasms; Cell Line, Tumor; Benzoquinones; Animals; Humans; HSP90 Heat-Shock Proteins; Proto-Oncogene Proteins c-akt

Although radical cystectomy with urinary diversion is the standard treatment for muscle-invasive bladder cancer (MIBC), loss of native bladder frequently impairs patient's quality of life (QOL). Bladder-sparing approach incorporating chemoradiotherapy (CRT) improves QOL while not compromising survival outcomes in MIBC patients. In this approach, complete response to induction CRT is a prerequisite for bladder preservation and favorable oncological outcomes. We investigated a strategy to potentiate CRT response of bladder cancer cells by using Hsp90 inhibitors in preclinical models. Hsp90 inhibitors at low concentrations, which did not exert cytocidal effects but inactivated key anti-apoptotic proteins including erbB2, Akt, and NF-κB, efficiently sensitized bladder cancer cells (T24, 5637 and UM-UC-3 cells) to in vitro CRT by enhancing apoptosis. Importantly, the sensitizing effects were not observed in primarily cultured normal human urothelial cells. We also showed that CRT induces accumulation of nuclear phospho-Akt, which antagonizes apoptosis, and that Hsp90 inhibitors block the cellular process. Hsp90 inhibition sensitized bladder cancer cells to in vitro CRT more effectively than sole or combined inhibition of erbB2 and Akt. In mice UM-UC-3 tumor xenografts model, Hsp90 inhibitors successfully potentiated anti-tumor activity of CRT. These results encourage clinical trials of Hsp90 inhibitors to overcome CRT resistance in patients with MIBC.