Small molecule BKM1972 inhibits human prostate cancer growth and overcomes docetaxel resistance in intraosseous models

Yanhua Chen, Lajos Gera, Shumin Zhang, Xin Li, Yang Yang, Kenza Mamouni, Alyssa Y. Wu, Hong Yan Liu, Omer Kucuk, Daqing Wu

Research output: Contribution to journalArticle

Abstract

Bone metastasis is a major cause of prostate cancer (PCa) mortality. Although docetaxel chemotherapy initially extends patients’ survival, in most cases PCa becomes chemoresistant and eventually progresses without a cure. In this study, we developed a novel small-molecule compound BKM1972, which exhibited potent in vitro cytotoxicity in PCa and other cancer cells regardless of their differences in chemo-responsiveness. Mechanistic studies demonstrated that BKM1972 effectively inhibited the expression of anti-apoptotic protein survivin and membrane-bound efflux pump ATP binding cassette B 1 (ABCB1, p-glycoprotein), presumably via signal transducer and activator of transcription 3 (Stat3). BKM1972 was well tolerated in mice and as a monotherapy, significantly inhibited the intraosseous growth of chemosensitive and chemoresistant PCa cells. These results indicate that BKM1972 is a promising small-molecule lead to treat PCa bone metastasis and overcome docetaxel resistance.

Original languageEnglish (US)
Pages (from-to)62-72
Number of pages11
JournalCancer Letters
Volume446
DOIs
StatePublished - Apr 1 2019

Fingerprint

docetaxel
Prostatic Neoplasms
Growth
Neoplasm Metastasis
STAT3 Transcription Factor
Bone Neoplasms
Apoptosis Regulatory Proteins
Glycoproteins
Adenosine Triphosphate
Bone and Bones
Drug Therapy
Membranes
Survival
Mortality

Keywords

  • Bone metastasis
  • Chemoresistance
  • Preclinical model
  • Prostate cancer
  • Small-molecule therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Small molecule BKM1972 inhibits human prostate cancer growth and overcomes docetaxel resistance in intraosseous models. / Chen, Yanhua; Gera, Lajos; Zhang, Shumin; Li, Xin; Yang, Yang; Mamouni, Kenza; Wu, Alyssa Y.; Liu, Hong Yan; Kucuk, Omer; Wu, Daqing.

In: Cancer Letters, Vol. 446, 01.04.2019, p. 62-72.

Research output: Contribution to journalArticle

Chen, Y, Gera, L, Zhang, S, Li, X, Yang, Y, Mamouni, K, Wu, AY, Liu, HY, Kucuk, O & Wu, D 2019, 'Small molecule BKM1972 inhibits human prostate cancer growth and overcomes docetaxel resistance in intraosseous models', Cancer Letters, vol. 446, pp. 62-72. https://doi.org/10.1016/j.canlet.2019.01.010
Chen, Yanhua ; Gera, Lajos ; Zhang, Shumin ; Li, Xin ; Yang, Yang ; Mamouni, Kenza ; Wu, Alyssa Y. ; Liu, Hong Yan ; Kucuk, Omer ; Wu, Daqing. / Small molecule BKM1972 inhibits human prostate cancer growth and overcomes docetaxel resistance in intraosseous models. In: Cancer Letters. 2019 ; Vol. 446. pp. 62-72.
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AU - Mamouni, Kenza

AU - Wu, Alyssa Y.

AU - Liu, Hong Yan

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AB - Bone metastasis is a major cause of prostate cancer (PCa) mortality. Although docetaxel chemotherapy initially extends patients’ survival, in most cases PCa becomes chemoresistant and eventually progresses without a cure. In this study, we developed a novel small-molecule compound BKM1972, which exhibited potent in vitro cytotoxicity in PCa and other cancer cells regardless of their differences in chemo-responsiveness. Mechanistic studies demonstrated that BKM1972 effectively inhibited the expression of anti-apoptotic protein survivin and membrane-bound efflux pump ATP binding cassette B 1 (ABCB1, p-glycoprotein), presumably via signal transducer and activator of transcription 3 (Stat3). BKM1972 was well tolerated in mice and as a monotherapy, significantly inhibited the intraosseous growth of chemosensitive and chemoresistant PCa cells. These results indicate that BKM1972 is a promising small-molecule lead to treat PCa bone metastasis and overcome docetaxel resistance.

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