title: Zoledronic acid but not somatostatin analogs exerts anti-tumor effects in a model of murine prostatic neuroendocrine carcinoma of the development of castration-resistant prostate cancer.
abstract: BACKGROUND
  Since neuroendocrine (NE) cells play an important role in the development of castration-resistant prostate cancer (CRPC), target therapy to NE cells should be considered for treating CRPC. We investigated the effects zoledronic acid (ZOL) and two somatostatin analogs (octreotide: SMS, and pasireotide: SOM) on an NE allograft (NE-10) and its cell line (NE-CS), which were established from the prostate of the LPB-Tag 12T-10 transgenic mouse.
  
  
  METHODS
  We examined the in vivo effects of ZOL, SMS and SOM as single agents and their combinations on subcutaneously inoculated NE-10 allografts and the in vitro effects on NE-CS cells. Apoptosis and cell cycle activity were assessed by immunohistochemistry using TdT-mediated dUTP-biotin nick-end labeling (TUNEL) and a Ki-67 antibody, respectively.
  
  
  RESULTS
  In vivo growth of NE-10 tumors treated with ZOL, ZOL plus SMS, or ZOL plus SOM was significantly inhibited compared to the control as a consequence of induction of apoptosis and cell cycle arrest. ZOL induced time- and dose-dependent inhibition of in vitro proliferation of NE-CS cells, but the somatostatin analogs (SMS and SOM) did not. ZOL also inhibited migration of NE-CS cells. These effects were caused by inhibition of Erk1/2 phosphorylation via impairment of prenylation of Ras.
  
  
  CONCLUSIONS
  ZOL, but not SMS or SOM, induced apoptosis and inhibition of proliferation and migration through impaired prenylation of Ras in NE carcinoma models. Our findings support the possibility that ZOL could be used in the early phase for controlling NE cells, which may trigger progression to CRPC.
authors.affiliation: Department of Urology, Sapporo Medical University School of Medicine, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Naoya
authors.initials: N
authors.lastname: Masumori
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Maeda
authors.forename: Ko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitamura
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirata
authors.forename: Taiji
authors.initials: T
authors.lastname: Tsukamoto
mesh_terms: D000728:Androgens / Q000172:deficiency; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015282:Octreotide / Q000494:pharmacology*; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017481:Receptors, Somatostatin / Q000235:genetics; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077211:Zoledronic Acid; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D017481:Receptors, Somatostatin; C492049:Sstr2 protein, mouse; D013004:Somatostatin; D000077211:Zoledronic Acid; C094573:somatostatin receptor 5; C517782:pasireotide; D018631:ras Proteins; D015282:Octreotide