title: 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.
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.
authors: Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors: Takashi
authors: T
authors: Ui
authors: Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors: Kazue
authors: K
authors: Morishima
authors: Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors: Shin
authors: S
authors: Saito
authors: Department of Pathology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors: Yuji
authors: Y
authors: Sakuma
authors: Department of Clinical Oncology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors: Hirofumi
authors: H
authors: Fujii
authors: Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors: Yoshinori
authors: Y
authors: Hosoya
authors: Division of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Shumpei
authors: S
authors: Ishikawa
authors: Division of Genome Science, Research Center for Advanced Science and Technology, the University of Tokyo, Meguro-ku, Tokyo 153-8904, Japan.
authors: Hiroyuki
authors: H
authors: Aburatani
authors: Department of Pathology, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Masashi
authors: M
authors: Fukayama
authors: Department of Pathology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors: Toshiro
authors: T
authors: Niki
authors: Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors: Yoshikazu
authors: Y
authors: Yasuda
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D000077277:Esophageal Squamous Cell Carcinoma; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C112765:tanespimycin; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D002945:Cisplatin