Abstract
Castration-resistant progression of prostate cancer after androgen deprivation therapies remains the most critical challenge in the clinical management of prostate cancer. Resurgent androgen receptor (AR) activity is an established driver of castration-resistant progression, and upregulation of the full-length AR (AR-FL) and constitutively-active AR splice variants (AR-Vs) has been implicated to contribute to the resurgent AR activity. We reported previously that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD) can reduce the abundance of both AR-FL and AR-Vs. In the present study, we further showed that the effect of PPD on AR expression and target genes was independent of androgen. PPD treatment resulted in a suppression of ligand-independent AR transactivation. Moreover, PPD delayed castration-resistant regrowth of LNCaP xenograft tumors after androgen deprivation and inhibited the growth of castration-resistant 22Rv1 xenograft tumors with endogenous expression of AR-FL and AR-Vs. This was accompanied by a decline in serum prostate-specific antigen levels as well as a decrease in AR levels and mitoses in the tumors. Notably, the 22Rv1 xenograft tumors were resistant to growth inhibition by the next-generation anti-androgen enzalutamide. The present study represents the first to show the preclinical efficacy of PPD in inhibiting castration-resistant progression and growth of prostate cancer. The findings provide a rationale for further developing PPD or its analogues for prostate cancer therapy.
Highlights
Androgen deprivation therapy, which disrupts androgen receptor (AR) signaling through castration or AR antagonists, is the first-line treatment for disseminated prostate cancer
Knocking down AR-FL or AR splice variants (AR-Vs) by shRNA in xenograft models can delay the progression of prostate cancer to castration resistance and/or suppress the growth of prostate tumor that has already progressed to the castration-resistant state [15,30,31]
We examined the effect of PPD on the mRNA levels of different AR isoforms in these cells cultured in androgen-deprived condition by Quantitative Reverse Transcription-PCR (qRT-PCR)
Summary
Androgen deprivation therapy, which disrupts androgen receptor (AR) signaling through castration or AR antagonists, is the first-line treatment for disseminated prostate cancer. Several new drugs targeting AR reactivation in CRPC have been developed, and two of these have been approved by the FDA for treatment of metastatic CRPC, i.e., the androgen biosynthesis inhibitor abiraterone and the potent AR antagonist enzalutamide [18,19]. They heralded a new era of prostate cancer therapy. Increased expression of AR-Vs was shown to confer castration-resistant growth of prostate tumors [14,15,26,27,28], and to correlate with poor survival of CRPC patients [29]. Therapeutic approaches that can diminish the availability of both AR-FL and AR-Vs should offer considerable benefit in preventing and inhibiting prostate cancer recurrence after androgen deprivation therapy
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