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Preclinical evaluation of vitamin D and ginsenoside metabolites in combination for prostate cancer therapy : pharmacokinetic and pharmacodynamic interactions

University of British Columbia

The potential therapeutic roles of calcitriol as well as 20(S)-protopanaxadiol (aPPD), a naturally derived ginsenoside, have gained much attention in recent years for the prevention/treatment of prostate cancer (PCa). The clinical utility of calcitriol as an anticancer agent has been severely limited by its hypercalcemia related toxicity. The research presented here explores the pre-clinical efficacy of aPPD as a single agent and in combination with calcitriol in vitro and in the androgen insensitive castration resistant C4-2 human xenograft model prepared in mice to represent PCa in vivo. We further examined aPPD and calcitriol pharmacokinetic (PK) and pharmacodynamic based interactions. Calcitriol sensitizes PCa cells to aPPD-mediated anticancer effects by enhancing its ability to induce apoptosis and reduce cell proliferation in vitro (IC50 of aPPD is reduced by almost 12- and 18-fold in LNCaP and C4-2 cells, respectively). An LC/MS assay for calcitriol was optimized and used in PK studies carried out in CD-1, non-tumor bearing, and C4-2 tumor bearing nude mice. The amount of calcitriol reaching the blood was significantly increased by co-administration of aPPD and calcitriol oral clearance was reduced. The novel findings described herein indicate aPPD potently inhibits PCa in vivo partly via inhibition of a site on the AR N-terminal domain. This manifested as cell cycle arrest and concurrent induction of apoptosis via an increase in Bax, cleaved-caspase-3, p27 and p21 expression in C4-2 tumors. Furthermore, aPPD significantly decreased Ki-67 and AR protein expression in xenograft tumors, while upregulating VDR. Adding calcitriol to aPPD treatments resulted in substantially greater inhibition of C4-2 growth than aPPD treated alone (76 % vs 53%, respectively). In the presence of calcitriol, aPPD enhanced significantly calcitriol mediated VDR activation while aPPD treatments alone did not affect the VDR activity, suggesting that aPPD may be an allosteric activator of VDR. Our findings encourage use of lower dose calcitriol in combination with aPPD to establish therapeutic benefit while limiting side-effects such as calcitriol associated hypercalcemia. Inhibition of the AR signaling pathway alongside increased associated enhancement of VDR expression and activation with increased calcitriol serum exposure are likely to be mechanistically associated with this sensitization effect.

Text

2018-07-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/66608

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/