title: YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts.
abstract: Various accumulating evidence suggests that survivin, a member of the inhibitor of apoptosis (IAP) family, plays an important role in drug resistance and cancer cell survival in many types of cancer, including hormone-refractory prostate cancer (HRPC). Here, we characterized YM155, a novel small-molecule survivin suppressant, using a survivin gene promoter activity assay. YM155 suppressed expression of survivin and induced apoptosis in PC-3 and PPC-1 human HRPC cell lines at 10 nmol/L. In contrast, YM155 up to 100 nmol/L showed little effect on expression levels of other IAP- or Bcl-2-related proteins. In a s.c. xenografted PC-3 tumor model in mice, 3-day continuous infusions of YM155 at 3 to 10 mg/kg induced massive tumor regression accompanied by suppression of intratumoral survivin. YM155 also completely inhibited the growth of orthotopically xenografted PC-3 tumors. No significant decreases in body weight were observed in mice treated with YM155 during the experimental period. Pharmacokinetic analyses indicated that YM155 is highly distributed to tumors and at concentrations approximately 20-fold higher than those in plasma. Our findings represent the first attempt to show tumor regression and suppression of survivin in p53-deficient human HRPC cells by a single small molecular compound treatment. Further extensive investigation of YM155 in many types of cancer, including HRPC, seems to be worthwhile to develop this novel therapeutic approach.
authors.affiliation: Institute for Drug Discovery Research, Astellas Pharma Inc, Tsukuba-Shi, Ibaraki, Japan. takahito.nakahara@jp.astellas.com
authors.forename: Takahito
authors.initials: T
authors.lastname: Nakahara
authors.forename: Aya
authors.initials: A
authors.lastname: Kita
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamanaka
authors.forename: Masamichi
authors.initials: M
authors.lastname: Mori
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Amino
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Fumiko
authors.initials: F
authors.lastname: Tominaga
authors.forename: Shinji
authors.initials: S
authors.lastname: Hatakeyama
authors.forename: Isao
authors.initials: I
authors.lastname: Kinoyama
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuhisa
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kudoh
authors.forename: Masao
authors.initials: M
authors.lastname: Sasamata
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D016466:CHO Cells; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D009285:Naphthoquinones / Q000494:pharmacology* / Q000627:therapeutic use*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012074:Remission Induction; D000077022:Survivin; D017211:Treatment Failure; D047368:Tumor Burden / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays