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.

Repositioning Dopamine D2 Receptor Agonist Bromocriptine to Enhance Docetaxel Chemotherapy and Treat Bone Metastatic Prostate Cancer

“…Docetaxel treatment also suppressed p-CREB expression ( p < 0.001), with no significant effects on the levels of DRD2 or AR. Interestingly, survivin was slightly elevated in the tissues treated with docetaxel, an effect we have observed previously (31). The combination treatment resulted in increased expression of DRD2 ( p = 0.02) and decreased level of p-CREB ( p = 0.001) in bone tumors.…”

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

“…Previously, we provided the first evidence indicating a positive correlation between survivin expression and clinical PCa bone metastasis, an observation supported by other studies [10][11][12]. We further showed that inhibition of survivin by small molecules or natural compounds could sensitize PCa cells to docetaxel treatment, resulting a synergistic suppression of tumor growth in mouse skeletons [13,14]. These results indicate that targeting survivin is a promising strategy to overcome therapeutic resistance and treat PCa bone metastasis.…”

“…Overexpression of survivin has been associated with clinical PCa bone metastasis [11,12]. In previous studies, we observed an increase in survivin expression following docetaxel treatment, and inhibition of survivin antagonized this inductive effect of docetaxel and sensitized PCa cells to chemotherapy [13,14]. These results indicate that survivin-targeted strategy could be a promising approach to overcome docetaxel chemoresistance and treat PCa bone metastasis.…”

“…We have developed several bradykinin antagonist mimetics (BKM) and demonstrated their anticancer activities in the experimental models of lung cancer, ovarian cancer, glioblastoma and PCa [11,14,[22][23][24][25]. Herein, we report that BKM1972, a novel BKM compound with an aminobisphosphonate moiety, exhibits unique activities against the in vitro and in vivo growth of bone metastatic PCa cells.…”

Sensitive liquid chromatography/tandem mass spectrometry method for the determination of two novel highly lipophilic anticancer drug candidates in rat plasma and tissues

“…Amino-bisphosphonate derivatives are another group of novel small-molecules, designed for targeting bone metastatic prostate cancer. These compounds have been shown to effectively inhibit tumor growth in bone, reduce prostate-specific antigens and improve bone structure in animal studies (Gera et al , 2008; Seo et al , 2008; Sh. Zhang et al , 2016).…”