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

Il Seo Seong, Lajos Gera, Haiyen E. Zhau, Ping Qian Wei, Shareen Iqbal, Nicole A. Johnson, Shumin Zhang, Majd Zayzafoon, John Stewart, Ruoxiang Wang, Leland W.K. Chung, Daqing Wu

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 ARCaPM 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.

Original languageEnglish (US)
Pages (from-to)6198-6206
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number19
DOIs
StatePublished - Oct 1 2008

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Bone Development
Diphosphonates
Prostatic Neoplasms
Apoptosis
Bone and Bones
Neoplasm Metastasis
Prostate-Specific Antigen
Nude Mice
Growth
Neoplasms
tyrosinamide
1-((N-(2,3,4,5,6-pentafluorocinnamoyl)-O-(2,6-dichlorobenzyl))tyrosyl)-4-(bis(diethoxyphosphono))methylaminiopiperidine
Serum
Tibia
Radiography
Research Design
Theoretical Models
Cell Line
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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

In: Clinical Cancer Research, Vol. 14, No. 19, 01.10.2008, p. 6198-6206.

Research output: Contribution to journalArticle

Seong, IS, Gera, L, Zhau, HE, Wei, PQ, Iqbal, S, Johnson, NA, Zhang, S, Zayzafoon, M, Stewart, J, Wang, R, Chung, LWK & Wu, D 2008, 'BKM1740, an acyl-tyrosine bisphosphonate amide derivative, inhibits the bone metastatic growth of human prostate cancer cells by inducing apoptosis', Clinical Cancer Research, vol. 14, no. 19, pp. 6198-6206. https://doi.org/10.1158/1078-0432.CCR-08-1023
Seong, Il Seo ; Gera, Lajos ; Zhau, Haiyen E. ; Wei, Ping Qian ; Iqbal, Shareen ; Johnson, Nicole A. ; Zhang, Shumin ; Zayzafoon, Majd ; Stewart, John ; Wang, Ruoxiang ; Chung, Leland W.K. ; Wu, Daqing. / BKM1740, an acyl-tyrosine bisphosphonate amide derivative, inhibits the bone metastatic growth of human prostate cancer cells by inducing apoptosis. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 19. pp. 6198-6206.
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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 ARCaPM 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.",
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T1 - BKM1740, an acyl-tyrosine bisphosphonate amide derivative, inhibits the bone metastatic growth of human prostate cancer cells by inducing apoptosis

AU - Seong, Il Seo

AU - Gera, Lajos

AU - Zhau, Haiyen E.

AU - Wei, Ping Qian

AU - Iqbal, Shareen

AU - Johnson, Nicole A.

AU - Zhang, Shumin

AU - Zayzafoon, Majd

AU - Stewart, John

AU - Wang, Ruoxiang

AU - Chung, Leland W.K.

AU - Wu, Daqing

PY - 2008/10/1

Y1 - 2008/10/1

N2 - 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 ARCaPM 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.

AB - 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 ARCaPM 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.

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EP - 6206

JO - Clinical Cancer Research

JF - Clinical Cancer Research

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