title: YM155 reverses rapamycin resistance in renal cancer by decreasing survivin.
abstract: OBJECTIVE
  Mammalian target of rapamycin inhibitor has exhibited promising anticancer activity for the treatment of renal cell carcinoma (RCC). However, many patients acquire resistance to therapeutic agents leading to treatment failure. The objective of this study was to determine whether treatment with YM155, a novel small molecule inhibitor of survivin, could reverse rapamycin resistance in a rapamycin-resistant RCC.
  
  
  METHODS
  We induced a rapamycin-resistant clear cell carcinoma cell line (Caki-1-RapR). We showed that survivin gene expression was significantly up-regulated in Caki-1-RapR compared with that in its parent cells (Caki-1). Therefore, we hypothesized that targeting of survivin in Caki-1-RapR could reverse the resistant phenotype in tumor cells, thereby enhancing the therapeutic efficacy of rapamycin. We used both in vitro and in vivo models to test the efficacy of YM155 either as a single agent or in combination with rapamycin.
  
  
  RESULTS
  In Caki-1-RapR cells, YM155 significantly decreased survivin gene and protein expression levels and cell proliferation in a dose-dependent manner in vitro. In addition, YM155 treatment significantly reversed rapamycin resistance in cancer cells. In a nude mouse tumor xenograft model, YM155 significantly inhibited the growth of Caki-1-RapR tumor. In addition, YM155 significantly enhanced the antitumor effects of rapamycin in Caki-1-RapR tumor.
  
  
  CONCLUSIONS
  Our results suggest a potentially novel strategy to use YM155 to overcome the resistance in tumor cells, thereby enhancing the effectiveness of molecular target therapy in RCC.
authors.affiliation: Department of Urology, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi, 371-8511, Japan, hkoike@gunma-u.ac.jp.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Koike
authors.forename: Takashi
authors.initials: T
authors.lastname: Nitta
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekine
authors.forename: Seiji
authors.initials: S
authors.lastname: Arai
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Furuya
authors.forename: Masashi
authors.initials: M
authors.lastname: Nomura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsui
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shibata
authors.forename: Kazuto
authors.initials: K
authors.lastname: Ito
authors.forename: Tetsunari
authors.initials: T
authors.lastname: Oyama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000187:drug effects / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009285:Naphthoquinones / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology*; D000077022:Survivin; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D000077022:Survivin; C523798:sepantronium; D020123:Sirolimus