title: Antitumor activity of YM155, a selective small-molecule survivin suppressant, alone and in combination with docetaxel in human malignant melanoma models.
abstract: OBJECTIVE
  Aggressive cell growth and chemoresistance are notorious obstacles in melanoma therapy. Accumulating evidence suggests that survivin is preferentially expressed in cancer cells and plays a crucial role in cell division and apoptosis dysfunction. Here, we evaluated the therapeutic potential of YM155, a selective survivin suppressant, alone and in combination with docetaxel using human melanoma models.
  
  
  METHODS
  A375 and SK-MEL-5 human malignant melanoma cells were treated with siRNA, YM155, and/or docetaxel, and cell viability, mRNA and protein expression levels, cell-cycle distribution, and immunohistochemical staining were then evaluated. Furthermore, the efficacy of YM155 combined with docetaxel was further examined in established xenograft models.
  
  
  RESULTS
  Survivin suppression was sufficient to induce spontaneous apoptosis of melanoma cells. YM155 showed nanomolar antiproliferative effects and induced tumor regression in established melanoma xenograft models. Docetaxel showed antitumor activity against melanoma cells, although it also induced survivin upregulation and G(2)/M mitotic arrest; however, cotreatment with YM155 decreased survivin expression below basal levels. Combination treatment of YM155 and docetaxel induced a greater rate of apoptosis than the sum of the single-treatment rates and promoted tumor regression without enhanced body weight loss in the melanoma xenograft models.
  
  
  CONCLUSIONS
  Survivin is responsible for the inherent low levels of spontaneous apoptosis in melanoma cells. The concomitant combination of YM155 with docetaxel diminished the accumulation of survivin in G(2)/M mitotic arrest, and induced more intense apoptosis compared with each single treatment. YM155 in combination with docetaxel is well tolerated and shows greater efficacy than either agent alone in mouse xenograft models.
authors: Drug Discovery Research, Astellas Pharma, Inc., Tsukuba-shi, Ibaraki, Japan.
authors: Kentaro
authors: K
authors: Yamanaka
authors: Takahito
authors: T
authors: Nakahara
authors: Tomohiro
authors: T
authors: Yamauchi
authors: Aya
authors: A
authors: Kita
authors: Masahiro
authors: M
authors: Takeuchi
authors: Fumiko
authors: F
authors: Kiyonaga
authors: Naoki
authors: N
authors: Kaneko
authors: Masao
authors: M
authors: Sasamata
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009285:Naphthoquinones / Q000008:administration & dosage / Q000494:pharmacology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D000077022:Survivin; D043823:Taxoids; D000077143:Docetaxel; D053148:Caspase 3; D053179:Caspase 7; C523798:sepantronium