Cytochrome P450 17A1 Inhibitor Abiraterone Acetate Counteracts the Heat Shock Protein 27's Cell Survival Properties in Prostate Cancer Cells

Abstract

Introduction: Inhibition of androgen synthesis by abiraterone acetate (AA) entails enhanced overall survival rates and clinical benefit for patients with locally advanced and metastasized prostate cancer (PC). The expression of heat shock protein 27 (HSP27) is generally associated with cytoprotection and was demonstrated to mediate chemoresistance under cytostatic therapy, for instance, docetaxel treatment. In this study, we investigated the impact of AA treatment on HSP27 expression and PC cell growth. Materials and Methods: HSP27 expression levels in docetaxel and AA-treated PC cell lines LNCaP and PC-3 were determined by SDS PAGE and Western blot analysis. Proliferation assays were performed using a CASY Cell Counter and Analyzer Model TT (Roche Applied Science). Results: Despite significantly increased HSP27 expression in PC cells incubated with docetaxel, Western blot analysis implicated a significant reduction of the cytoprotective HSP27 in AA-treated PC cells. Notably, HSP27 stably overexpressed in PC-3-HSP27 cells did not appear as an HSP27-mediated proliferation benefit in the presence of AA as shown in docetaxel incubation studies. Conclusion: In contrast to repeatedly demonstrated HSP27-driven chemoresistance related to chemotherapeutics, our results may constitute a broader molecular mode of action of AA chemotherapy. AA efficacy may exert an HSP27 suppressive role that goes beyond the primarily assumed inhibition of androgen biosynthesis.

The androgen receptor antagonist enzalutamide induces apoptosis, dysregulates the heat shock protein system, and diminishes the androgen receptor and estrogen receptor β1 expression in prostate cancer cells

“…In the present study, we have demonstrated that enzalutamide attenuates the proliferation of PC cells in a time‐ and dose‐dependent manner, demonstrating different drug sensitivities of the cell lines. These data are supported by previous studies using a similar experimental approach, such as PC cell growth inhibition by abiraterone, in vitro treatment of PC with enzalutamide, and mouse xenograft models …”

“…In the present study, we have demonstrated that enzalutamide attenuates the proliferation of PC cells in a time-and dose-dependent manner, demonstrating different drug sensitivities of the cell lines. These data are supported by previous studies using a similar experimental approach, such as PC cell growth inhibition by abiraterone, [27][28][29][30] in vitro treatment of PC with enzalutamide, and mouse xenograft models. 7,[31][32][33] Growth-inhibitory effects during anticancer therapy has been shown to be often accompanied by an increase of p53 protein, which acts in surveillance of genomic integrity and oncogene activity.…”

Promising Tools in Prostate Cancer Research: Selective Non-Steroidal Cytochrome P450 17A1 Inhibitors

“…Furthermore, abiraterone inhibits CYP21A2 30 and CYP11B1 9 which in the clinical setting, forces co-administration of prednisone to mitigate the resulting mineralocorticoid excess 30 . Besides the effects from the binding of abiraterone to CYP enzymes, it may have several other anticancer effects, involving binding to the androgen receptor, 3β‐hydroxysteroid dehydrogenase inhibition as well as decreasing the levels of heat shock protein 27, a cytoprotective agent involved in drug resistance issues, in androgen-insensitive prostate cancer cells 31 . Although these types of effects may be favourable, a selectively binding compound could reduce the risk of adverse side effects and can additionally be used as pharmacological tools in prostate cancer research.…”