Calcitriol and 20(S)-protopanaxadiol synergistically inhibit growth and induce apoptosis in human prostate cancer cells: Beyond The Abstract

Due to the hypercalcemic side effects of vitamin D and its derivatives in higher plasma concentrations, the anti-cancer benefits of calcitriol (the active form of vitamin D) have not been fully realized in prostate cancer (PCa) chemoprevention and/or treatment. From our experience in natural health product research, it is evident that tissue-specific sensitization of vitamin D actions by concomitant use of natural products is an effective way of blocking the development or progression of PCa.


We have identified that a class of naturally derived ginsenoside molecules that not only inhibit the cytochrome P450-mediated catabolism and deactivation of calcitriol (Deb et al., 2014), but also target key cell signaling pathways involving androgen receptor (AR) and steroidogenesis known to be dysregulated in PCa while enhancing vitamin D receptor (VDR) expression. VDR has been shown to have an anti-cancer role and so enhancing its expression/activation may be particularly relevant in the treatment of PCa (Ahn, Park et al. 2016, Ben-Eltriki, Deb et al. 2016).

By virtue of their multi-targeting potential, it is not surprising that ginsenosides have highly pleiotropic therapeutic activities and of current clinical relevance. A series of ginsenoside analogs, structurally based on 20(s)-protopanaxadiol (aPPD) (known as drug entity S111 in China) that has already been used as an antidepressant in humans in China, have been synthesized through a combinatorial chemistry approach developed by the Shanghai Innovative Research Centre of Traditional Chinese Medicine (SIRC). Combining calcitriol with aPPD (S111) is logical for many reasons: low vitamin D levels are known to be a contributing cause of depression, immune disorders, endocrine-related cancers as well as increasing the risk of developing cancers of the colon, ovary, lung, breast and prostate. The fact that aPPD exhibited good efficacy in inhibiting AR and its splice variants, major factors driving PCa growth and progression, highlights the potential of aPPD in PCa prevention and/or therapy (Cao, Liu et al. 2013, Cao, Qi et al. 2014).

Importantly, preliminary results in our laboratory determined that aPPD has the ability to inhibit CYP17A1 and CYP11A1, which are the vital enzymes for androgen synthesis from cholesterol in castration resistant PCa (CRPCa). As a consequence aPPD may also inhibit de novo synthesis of androgens, a known treatment resistance phenomenon observed in advanced CRPCa patients.  In addition, there is now considerable evidence to suggest that crosstalk exists between VDR and AR. This may vary between different PCa cell lines and could be mediated via sharing of coregulators required for receptor activation. Several AR coregulators including ARA54, ARA70, gelsolin, and supervillin, have been reported to modulate other steroid receptors and promote VDR function (Ting, Bao et al. 2005). In addition, we have also shown that aPPD treatment led to inhibition of enzyme-mediated inactivation of calcitriol in human liver microsomes in vitro, potentially providing additional vitamin D-related benefits to patients with cancer, neurodegenerative and metabolic diseases (Deb, Chin et al. 2014).

Preclinical pharmacokinetic studies from our laboratory have convincingly demonstrated that ginsenosides can reach to the prostate tumor site (Musende et al., 2009, 2012) and can potentially alter the prostate levels of calcitriol during the synergistic anti-cancer effects of this combination. In the presence of aPPD, the removal of calcitriol from the cell culture medium is delayed, which suggests that intratumoral calcitriol level in the presence of aPPD is possibly increased and can be one of the crucial factors in sensitizing the vitamin D actions in PCa. Furthermore, it has been shown that both ginsenosides and calcitriol can induce apoptosis and cause cell cycle arrest independently. Here, for the first time, the results clearly indicate that this combination is promising as a therapeutic strategy since it offers a contemporary approach to maximize the multifaceted biological and therapeutic actions of vitamin D at a lower dose when combined with ginsenoside metabolites in the context of PCa. The chemosensitization of calcitriol actions at clinically relevant concentrations by aPPD is a highly promising approach for PCa chemoprevention as well as treatment.

Written by: Mohamed Ben-Eltriki, Subrata Deb and Emma S. Tomlinson Guns
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References:

Ahn, J., S. Park, B. Zuniga, A. Bera, C. S. Song and B. Chatterjee (2016). "Vitamin D in Prostate Cancer." Vitam Horm 100: 321-355.

Ben-Eltriki, M., S. Deb and E. S. Tomlinson Guns (2016). "Calcitriol in combination therapy for prostate cancer: pharmacokinetic and pharmacodynamic interactions. ." Journal of Cancer 4(7): 391-407.

Cao, B., X. Liu, J. Li, S. Liu, Y. Qi, Z. Xiong, A. Zhang, T. Wiese, X. Fu, J. Gu, P. S. Rennie, O. Sartor, B. R. Lee, C. Ip, L. Zhao, H. Zhang and Y. Dong (2013). "20(S)-protopanaxadiol-aglycone downregulation of the full-length and splice variants of androgen receptor." Int J Cancer 132(6): 1277-1287.

Cao, B., Y. Qi, Y. Yang, X. Liu, D. Xu, W. Guo, Y. Zhan, Z. Xiong, A. Zhang, A. R. Wang, X. Fu, H. Zhang, L. Zhao, J. Gu and Y. Dong (2014). "20(S)-protopanaxadiol inhibition of progression and growth of castration-resistant prostate cancer." PLoS One 9(11): e111201.

Deb, S., M. Y. Chin, H. Adomat and E. S. Guns (2014). "Ginsenoside-mediated blockade of 1alpha,25-dihydroxyvitamin D inactivation in human liver and intestine in vitro." J Steroid Biochem Mol Biol 141C: 94-103.

Ting, H. J., B. Y. Bao, C. L. Hsu and Y. F. Lee (2005). "Androgen-receptor coregulators mediate the suppressive effect of androgen signals on vitamin D receptor activity." Endocrine 26(1): 1-9.
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