BKM1740, an acyl-tyrosine bisphosphonate amide derivative, inhibits the bone metastatic growth of human prostate cancer cells by inducing apoptosis.
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.
Seo
Seong Il
SI
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.
Gera
Lajos
L
Zhau
Haiyen E
HE
Qian
Wei Ping
WP
Iqbal
Shareen
S
Johnson
Nicole A
NA
Zhang
Shumin
S
Zayzafoon
Majd
M
Stewart
John
J
Wang
Ruoxiang
R
Chung
Leland W K
LW
Wu
Daqing
D
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
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