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

• Authors: Yanhua Chen, Huazhong University of Science & Technology; Lajos Gera, University of Colorado Denver; Shumin Zhang, Emory University; Xin Li, Augusta University; Yang Yang, Augusta University; Kenza Mamouni, Augusta University; Alyssa Y. Wu, Chamblee Charter High School; HongYan Liu, Augusta University; Omer Kucuk, Emory University; Daqing Wu, Emory University
• Journal Title: CANCER LETTERS
• Volume: Volume 446
• Publisher: ELSEVIER IRELAND LTD | 2019-01-01, Pages 62-72
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.canlet.2019.01.010
• Subjects: Health Sciences, Oncology; Biology, Genetics; Health Sciences, Medicine and Surgery
• 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

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.