title: Sunitinib malate synergistically potentiates anti-tumor effect of gemcitabine in human bladder cancer cells.
abstract: OBJECTIVE
  Sunitinib malate (Sutent; Pfizer, New York, NY, USA) is a highly selective multi-targeted agent and has been reported to have potent anti-tumor effects against various tumors, including renal cell carcinoma and gastrointestinal stromal tumors. In this study, we explored in vitro the anti-tumor effect and related molecular mechanisms of sunitinib malate against human bladder cancer cell lines. We also determined the synergistic anti-tumor effect between sunitinib and conventional cytotoxic drugs, cisplatin and gemcitabine, in bladder cancer cells.
  
  
  METHODS
  Six human cancer cell lines (HTB5, HTB9, T24, UMUC14, SW1710, and J82) were exposed to an escalating dose of sunitinib alone or in combination with cisplatin/gemcitabine, and the cytotoxic effect of the drugs was examined by CCK-8 assay. The synergistic effect between sunitinib and cisplatin/gemcitabine was determined by the combination index (CI) and clonogenic assay. Alterations in cell cycle (cyclin D, B1), survival (p-Akt, t-Akt), and apoptosis (Bax, Bad) regulator expression were analyzed by Western blotting.
  
  
  RESULTS
  Like cisplatin and gemcitabine, sunitinib exerted a dose- and time-dependent anti-tumor effect in bladder cancer cells. However, sunitinib exhibited entirely different sensitivity profiles from cisplatin and gemcitabine. Sunitinib suppressed the expression of cyclin B1, p-Akt, and t-Akt while augmenting the expression of cyclin D and pro-apoptotic Bax and Bad in HTB5 cells. Analysis of the drug combination by the isobolic method and clonogenic assay revealed that sunitinib acts in synergy with gemcitabine in HTB5 cells.
  
  
  CONCLUSIONS
  These results indicate that sunitinib malate has a potent anti-tumor effect and may synergistically enhance the anti-tumor effect of gemcitabine in human bladder cancer cells.
authors.affiliation: Department of Urology, Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
authors.forename: Cheol Yong
authors.initials: CY
authors.lastname: Yoon
authors.forename: Jung Sun
authors.initials: JS
authors.lastname: Lee
authors.forename: Bo Sun
authors.initials: BS
authors.lastname: Kim
authors.forename: Seong Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Sung Kyu
authors.initials: SK
authors.lastname: Hong
authors.forename: Seok Soo
authors.initials: SS
authors.lastname: Byun
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Lee