title: MK2206 potentiates cisplatin-induced cytotoxicity and apoptosis through an interaction of inactivated Akt signaling pathway.
abstract: OBJECTIVE
  To improve conventional chemotherapeutic efficacy, it is important to detect new molecular markers for chemosensitivity and possible accelerating cell-killing mechanisms. In this study, we investigated how MK2206, an allosteric Akt inhibitor, enhances the cisplatin (CDDP)-induced cytotoxicity and apoptosis in urothelial cancer cells.
  
  
  METHODS
  We examined bladder cancer cell lines for the expression of phospho(p)-Akt and its downstream targets by Western blot. The potential antitumor effects were analyzed by MTT assay in vitro and by subcutaneous xenograft models in vivo. The cell invasion was examined by transwell invasion assay, and the activities of the Akt signaling pathway and expression of apoptosis-related proteins were measured by Western blot.
  
  
  RESULTS
  The expression of p-Akt and its downstream targets was increased in invasive bladder cancer cell lines vs. in noninvasive bladder cancer cell lines. MK2206 (500 nM) inhibited cell invasion in UMUC3 cell line and significantly increased the susceptibility of bladder cancer cell lines to CDDP. When used in combination with CDDP, MK2206 (500 nM) enhanced CDDP-induced cytotoxicity and apoptosis, with suppressed expression of p-Akt and its downstream targets. In vivo MK2206 combined with CDDP effectively suppressed tumor growth in subcutaneous xenograft models.
  
  
  CONCLUSIONS
  These results suggest that concomitant use of MK2206 could promote the CDDP-induced cytotoxicity and apoptosis in urothelial cancer cell lines through the inhibited expression of the Akt pathway. This combined treatment may provide a new therapeutic option to enhance chemosensitivity in bladder cancer.
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Urology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, P R China.
authors.forename: Dingqi
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Atsuro
authors.initials: A
authors.lastname: Sawada
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ogawa
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: ym1108@kuhp.kyoto-u.ac.jp.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Matsui
mesh_terms: D000495:Allosteric Site; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000473:pathology; D019459:Urothelium / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin
keywords: Akt pathway; Cisplatin; Invasion; MK2206; Urothelial cancer