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

Cancer Lett. 2019 Apr 1:446:62-72. doi: 10.1016/j.canlet.2019.01.010. Epub 2019 Jan 18.

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.

Keywords: Bone metastasis; Chemoresistance; Preclinical model; Prostate cancer; Small-molecule therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / secondary
  • Bradykinin Receptor Antagonists / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Docetaxel / pharmacology*
  • Drug Resistance, Neoplasm*
  • Humans
  • Male
  • Mice, Nude
  • Molecular Targeted Therapy
  • Organophosphonates / pharmacology*
  • Phosphorylation
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Survivin / genetics
  • Survivin / metabolism
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Antineoplastic Agents
  • BIRC5 protein, human
  • Bradykinin Receptor Antagonists
  • Organophosphonates
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Survivin
  • Docetaxel