About this item:

44 Views | 4 Downloads

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Prostate cancer
  • Bone metastasis
  • Chemoresistance
  • Small-molecule therapy
  • Preclinical model
  • KINASE-C-EPSILON
  • BONE METASTATIC GROWTH
  • GENE-EXPRESSION
  • SURVIVIN GENE
  • CELL-LINES
  • CONSTITUTIVE ACTIVATION
  • MDR1 GENE
  • STAT3
  • LNCAP
  • MECHANISMS

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

Tools:

Journal Title:

CANCER LETTERS

Volume:

Volume 446, Number

Publisher:

, Pages 62-72

Type of Work:

Article

Abstract:

© 2019 Elsevier B.V. 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.
Export to EndNote