title: Inhibition of skeletal growth of human prostate cancer by the combination of docetaxel and BKM1644: an aminobisphosphonate derivative.
abstract: 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.
authors.affiliation: Department of Urology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Shumin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Anschutz Medical Campus, School of Medicine, Aurora, CO, USA.
authors.forename: Lajos
authors.initials: L
authors.lastname: Gera
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia and GRU Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Kenza
authors.initials: K
authors.lastname: Mamouni
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia and GRU Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Omer
authors.initials: O
authors.lastname: Kucuk
authors.affiliation: Department of Urology, Emory University School of Medicine, Atlanta, GA, USA.|Department of Biochemistry and Molecular Biology, Medical College of Georgia and GRU Cancer Center, Augusta University, Augusta, GA, USA.|MetCure Therapeutics LLC, Atlanta, GA, USA.
authors.forename: Daqing
authors.initials: D
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D000077143:Docetaxel; D004347:Drug Interactions; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011897:Random Allocation; D043823:Taxoids / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D043823:Taxoids; D000077143:Docetaxel
keywords: bone metastasis; docetaxel resistance; preclinical models; prostate cancer; survivin inhibitor