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.
Highlights
The American Cancer Society estimated that 180,890 patients will be diagnosed with prostate cancer (PCa) in 2016, and 26,120 will die, mostly from metastatic castration-resistant PCa [1]
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
The average GI50 (50% growth inhibition) in the NCI-60 panel is 1.4 μM, and the average LC50 (50% lethal concentration) is 3.0 μM
Summary
The American Cancer Society estimated that 180,890 patients will be diagnosed with prostate cancer (PCa) in 2016, and 26,120 will die, mostly from metastatic castration-resistant PCa (mCRPC) [1]. Current treatments, including chemotherapy using docetaxel and cabazitaxel, initially prolong the median survival by 3~5 months, patients generally relapse within a year and develop extremely resistant tumors [2, 3]. It is imperative to develop novel strategies to overcome therapeutic resistance and improve the survival of mCRPC patients [4,5,6]. Survivin-targeted therapy, could be a promising strategy to enhance standard treatment and improve overall survival of mCRPC patients. Various molecular approaches are currently under development; most only exhibit modest benefits in PCa patients with localized and metastatic diseases [16]
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