YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts.
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.
Nakahara
Takahito
T
Institute for Drug Discovery Research, Astellas Pharma Inc, Tsukuba-Shi, Ibaraki, Japan. takahito.nakahara@jp.astellas.com
Kita
Aya
A
Yamanaka
Kentaro
K
Mori
Masamichi
M
Amino
Nobuaki
N
Takeuchi
Masahiro
M
Tominaga
Fumiko
F
Hatakeyama
Shinji
S
Kinoyama
Isao
I
Matsuhisa
Akira
A
Kudoh
Masafumi
M
Sasamata
Masao
M
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