Bone metastasis is a major cause of prostate cancer (PCa) morbidity and mortality. Despite some success in transiently controlling clinical symptoms with docetaxel-based therapy, PCa patients become docetaxel-resistant and inevitably progress with no cure.
We synthesized an acyl-tyrosine bisphosphonate amide derivative, BKM1644, with the intent of targeting bone metastatic PCa and enhancing docetaxel's efficacy. BKM1644 exhibits potent anti-cancer activity in the NCI-60 panel and effectively inhibits the proliferation of metastatic, castration-resistant PCa (mCRPC) cells, with IC50 ranging between 2.1 μM and 6.3 μM. Significantly, BKM1644 sensitizes mCRPC cells to docetaxel treatment. Mice with pre-established C4-2 tumors in the tibia show a marked decrease in serum prostate-specific antigen (control: 173.72 ± 37.52 ng/ml, combined treatment: 64.45 ± 22.19 ng/ml; p < 0.0001) and much improved bone architecture after treatment with the combined regimen. Mechanistic studies found that docetaxel temporarily but significantly increases survivin, an anti-apoptotic protein whose overexpression has been correlated with PCa bone metastasis and therapeutic resistance. Intriguingly, BKM1644 effectively inhibits survivin expression, which may antagonize docetaxel-induced survivin in bone metastatic PCa cells. Signal transducer and activator of transcription 3 (Stat3) may be involved in the suppression of survivin transcription by BKM1644, as confirmed by a survivin reporter assay. Collectively, these data indicate that BKM1644 could be a promising small-molecule agent to improve docetaxel efficacy and retard the bone metastatic growth of PCa.
Oncotarget. 2016 Mar 30 [Epub ahead of print]
Shumin Zhang, Lajos Gera, Kenza Mamouni, Xin Li, Zhengjia Chen, Omer Kucuk, Daqing Wu
Department of Urology, Emory University School of Medicine, Atlanta, GA, USA., Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, School of Medicine, Aurora, CO, USA., Department of Biochemistry and Molecular Biology, Medical College of Georgia and GRU Cancer Center, Augusta University, Augusta, GA, USA., Department of Biochemistry and Molecular Biology, Medical College of Georgia and GRU Cancer Center, Augusta University, Augusta, GA, USA., Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA., Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA., Department of Urology, Emory University School of Medicine, Atlanta, GA, USA.