Abstract 1676: The HSP90 inhibitor 17-AAG improves chemoresistance of cisplatin-resistant esophageal squamous cell carcinoma cell lines

Abstract

Abstract [Background] Although cisplatin is a platinum drug that is widely used to treat esophageal squamous cell carcinoma, acquired chemoresistance develops during the course of treatment and is often the reason for treatment failure. Overcoming chemoresistance is essential for improving the outcomes of patients. Heat shock protein 90 (HSP90) is known to be overexpressed in various cancer cells, and its inhibition by small molecules, either alone or in combination, has shown promise in the treatment of solid malignancies. In the present study, we evaluated the synergistic effect of combining cisplatin with the HSP90 inhibitor, 17-N-allylamino-17-demethoxy geldanamycin (17-AAG), on two cisplatin-resistant human esophageal squamous cancer cell lines, KYSE30 and KYSE150. [Results] The results obtained demonstrated the synergistic inhibitory effects of cisplatin and 17-AAG on the growth of KYSE30 and KYSE150 cells. Cell growth and cell number were more effectively reduced by the combined treatment with cisplatin and 17-AAG than by the treatment with either cisplatin or 17-AAG alone. Western blotting revealed that the combined action of cisplatin and 17-AAG cleaved poly (ADP-ribose) polymerase (PARP) and caspase 3. Time lapse imaging revealed that the activations of caspase 3/7 preceded the cell death induced by the combined treatment of cisplatin and 17-AAG. These demonstrated that the reductions in both cell growth and cell number were mediated by apoptosis. Time-course experiments showed that reductions in X-linked inhibitor of apoptosis protein (XIAP) and phosphorylated Akt were concomitant with apoptosis. [Discussion] The results of the present study demonstrated that 17-AAG synergized with cisplatin and induced apoptosis in cisplatin-resistant esophageal squamous cell carcinoma cell lines, and also that modulation of the Akt/XIAP pathway may underlie this synergistic effect. [Conclusion] Combination therapy with cisplatin and a HSP90 inhibitor may represent a promising strategy to overcome cisplatin resistance in esophageal squamous cell carcinoma. Citation Format: Takashi Ui, Kazue Morishima, Shin Saito, Yuji Sakuma, Hirofumi Fujii, Yoshinori Hosoya, Yoshikazu Yasuda, Toshiro Niki. The HSP90 inhibitor 17-AAG improves chemoresistance of cisplatin-resistant esophageal squamous cell carcinoma cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1676. doi:10.1158/1538-7445.AM2014-1676