BKM1740, an acyl-tyrosine bisphosphonate amide derivative, inhibits the bone metastatic growth of human prostate cancer cells by inducing apoptosis.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Seong Il Seo, Lajos Gera, Haiyen E Zhau, Wei Ping Qian, Shareen Iqbal, Nicole A Johnson, Shumin Zhang, Majd Zayzafoon, John Stewart, Ruoxiang Wang, Leland W K Chung, Daqing Wu
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 19 Pg. 6198-206 (Oct 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18829499 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 1-((N-(2,3,4,5,6-pentafluorocinnamoyl)-O-(2,6-dichlorobenzyl))tyrosyl)-4-(bis(diethoxyphosphono))methylaminiopiperidine
• Amides
• Antineoplastic Agents
• Culture Media, Conditioned
• Diphosphonates
• Tyrosine

Topics

• Amides
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Bone Neoplasms (drug therapy, secondary)
• Cell Line, Tumor
• Cell Proliferation
• Culture Media, Conditioned (pharmacology)
• Diphosphonates (pharmacology)
• Flow Cytometry
• Humans
• Male
• Mice
• Neoplasm Metastasis
• Neoplasm Transplantation
• Prostatic Neoplasms (drug therapy, pathology)
• Tyrosine (analogs & derivatives, pharmacology)