The HSP90 inhibitor 17-N-allylamino-17-demethoxy geldanamycin (17-AAG) synergizes with cisplatin and induces apoptosis in cisplatin-resistant esophageal squamous cell carcinoma cell lines via the Akt/XIAP pathway

Ui,Takashi; Morishima,Kazue; Saito,Shin; Sakuma,Yuji; Fujii,Hirofumi; Hosoya,Yoshinori; Ishikawa,Shumpei; Aburatani,Hiroyuki; Fukayama,Masashi; Niki,Toshiro; Yasuda,Yoshikazu

doi:10.3892/or.2013.2899

The HSP90 inhibitor 17-N-allylamino-17-demethoxy geldanamycin (17-AAG) synergizes with cisplatin and induces apoptosis in cisplatin-resistant esophageal squamous cell carcinoma cell lines via the Akt/XIAP pathway

Authors:
- Takashi Ui
- Kazue Morishima
- Shin Saito
- Yuji Sakuma
- Hirofumi Fujii
- Yoshinori Hosoya
- Shumpei Ishikawa
- Hiroyuki Aburatani
- Masashi Fukayama
- Toshiro Niki
- Yoshikazu Yasuda
View Affiliations

Affiliations: Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan, Department of Pathology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan, Department of Clinical Oncology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan, Division of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan, Division of Genome Science, Research Center for Advanced Science and Technology, the University of Tokyo, Meguro-ku, Tokyo 153-8904, Japan, Department of Pathology, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
Published online on: December 5, 2013 https://doi.org/10.3892/or.2013.2899
Pages: 619-624

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Abstract

Although cisplatin (CDDP) is a key drug in the treatment of esophageal squamous cell carcinoma (ESCC), acquired chemoresistance remains a major problem. Combination therapy may represent one strategy to overcome this resistance. Heat shock protein 90 (HSP90) is known to be overexpressed in several types of 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 effects of combining CDDP with the HSP90 inhibitor 17-N-allylamino-17-demethoxy geldanamycin (17-AAG) on two CDDP-resistant human esophageal squamous cancer cell lines, KYSE30 and KYSE150. The results obtained demonstrated the synergistic inhibitory effects of CDDP 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 CDDP and 17-AAG than by the treatment with either CDDP or 17-AAG alone. Western blotting revealed that the combined action of CDDP and 17-AAG cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3, which demonstrated that the reduction in both cell growth and cell number was mediated by apoptosis. Time-course experiments showed that reduction in X-linked inhibitor of apoptosis protein (XIAP) and phosphorylated Akt were concomitant with apoptosis. The results of the present study demonstrate that 17-AAG synergizes with CDDP and induces apoptosis in CDDP-resistant ESCC cell lines, and also that modulation of the Akt/XIAP pathway may underlie this synergistic effect. Combination therapy with CDDP and an HSP90 inhibitor may represent a promising strategy to overcome CDDP resistance in ESCC.