title: BKM1740, an acyl-tyrosine bisphosphonate amide derivative, inhibits the bone metastatic growth of human prostate cancer cells by inducing apoptosis.
abstract: OBJECTIVE
  Survivin overexpression has been associated with an unfavorable outcome in human PCa; however, its role in metastasis remains elusive. We aim to (a) evaluate the clinical implications of survivin expression in PCa bone metastasis; (b) determine in vivo efficacy of BKM1740, a small-molecule compound, against PCa skeletal growth and survival; and (c) investigate molecular mechanism by which BKM1740 augments apoptosis in bone metastatic PCa cells.
  
  
  METHODS
  Survivin expression was analyzed in PCa specimens and experimental models. Bone metastatic C4-2 and ARCaP(M) cell lines were used to evaluate the in vitro effects of BKM1740 and molecular mechanism for the induction of apoptosis. C4-2 cells were grown intratibially in athymic nude mice to evaluate the in vivo efficacy of BKM1740. Tumor growth in mouse bone was assessed by serum prostate-specific antigen and radiography and confirmed by immunohistochemical analyses.
  
  
  RESULTS
  Survivin expression is positively associated with clinical PCa bone metastasis. BKM1740 induced apoptosis in PCa cells by repressing survivin. Mice with established C4-2 tumors in tibia showed a marked decrease in serum prostate-specific antigen and much improved bone architecture radiographically after treatment with BKM1740. Immunohistochemical assays of mouse tumor samples confirmed that the in vivo effects were mediated by inhibition of survivin and induction of apoptosis.
  
  
  CONCLUSIONS
  Survivin expression is associated with PCa bone metastasis. BKM1740 treatment specifically inhibited survivin and induced apoptosis in vitro and was efficacious in retarding PCa skeletal growth in a mouse model. BKM1740 is a promising small-molecule compound that could be used to treat PCa bone metastasis.
authors.affiliation: Molecular Urology and Therapeutics Program, Department of Urology and Winship Cancer Institute, Emory University School of Medicine, 1365-B C;ifton Road, Atlanta, GA 30322, USA.
authors.forename: Seong Il
authors.initials: SI
authors.lastname: Seo
authors.forename: Lajos
authors.initials: L
authors.lastname: Gera
authors.forename: Haiyen E
authors.initials: HE
authors.lastname: Zhau
authors.forename: Wei Ping
authors.initials: WP
authors.lastname: Qian
authors.forename: Shareen
authors.initials: S
authors.lastname: Iqbal
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Johnson
authors.forename: Shumin
authors.initials: S
authors.lastname: Zhang
authors.forename: Majd
authors.initials: M
authors.lastname: Zayzafoon
authors.forename: John
authors.initials: J
authors.lastname: Stewart
authors.forename: Ruoxiang
authors.initials: R
authors.lastname: Wang
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
authors.forename: Daqing
authors.initials: D
authors.lastname: Wu
mesh_terms: D000577:Amides; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005466:Fluorocarbons
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D004164:Diphosphonates; D014443:Tyrosine; C533033:1-((N-(2,3,4,5,6-pentafluorocinnamoyl)-O-(2,6-dichlorobenzyl))tyrosyl)-4-(bis(diethoxyphosphono))methylaminiopiperidine; D005466:Fluorocarbons