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 language | English (US) |
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Pages (from-to) | 62-72 |
Number of pages | 11 |
Journal | Cancer Letters |
Volume | 446 |
DOIs | |
State | Published - Apr 1 2019 |
Keywords
- Bone metastasis
- Chemoresistance
- Preclinical model
- Prostate cancer
- Small-molecule therapy
ASJC Scopus subject areas
- Oncology
- Cancer Research