Anti-Tumor Effects of Ginsenoside 20(S)-Protopanaxadiol and 1,25-Dihydroxyvitamin D3 Combination in Castration Resistant Prostate Cancer

Abstract

In spite of possessing desirable anticancer properties, currently, limited clinical success has been achieved with 20(S)-protopanaxadiol (aPPD) and 1,25-dihydroxyvitamin D3 (calcitriol). This study is designed to evaluate if the combination of aPPD with calcitriol can inhibit human prostate cancer xenograft growth by using nuclear receptor signaling. Athymic male nude mice were utilized to establish an androgen-independent human prostate cancer C4-2 cell castration-resistant prostate cancer (CRPC) xenograft model. Mice were treated orally for six weeks with 70 mg/kg aPPD administered once daily or three times per week with 4 µg/kg calcitriol or in combination or only with vehicle control. Contrary to our expectations, calcitriol treatment alone increased C4-2 tumor growth. However, the addition of calcitriol substantially increased aPPD-mediated tumor growth suppression (76% vs. 53%, combination vs. aPPD alone). The combination treatment significantly increased levels of cleaved caspase-3 apoptotic marker compared to vehicle-treated or aPPD-treated C4-2 tumors. The mechanistic elucidations indicate that tumor inhibition by the aPPD and calcitriol combination was accompanied by elevated vitamin D receptor (VDR) protein expression. In silico data suggest that aPPD weakly binds to the native LBD pocket of VDR. Interestingly, the combination of aPPD and calcitriol activated VDR at a significantly higher level than calcitriol alone and this indicates that aPPD may be an allosteric activator of VDR. Overall, aPPD and calcitriol combination significantly inhibited tumor growth in vivo with no acute or chronic toxic effects in the C4-2 xenograft CRPC nude mice. The involvement of VDR and downstream apoptotic pathways are potential mechanistic routes of antitumor effects of this combination.

Recent advances in dietary androgen receptor inhibitors

“…In a subsequent study, 20( S )‐protopanaxadiol effectively suppressed tumor growth, AR expression, and serum PSA in nude mice xenografted with castration‐resistant C4‐2 cells, partly through inhibiting AR NTD 225 . In recent years, the combination of 20( S )‐protopanaxadiol with 1α,25‐dihydroxyvitamin D3 was reported to suppress tumor growth in vivo, with limited or no toxicity 226,227 . Similarly, 20( S )‐ginsenoside Rh2 in combination with 1α,25‐dihydroxyvitamin D3 exerted additional anti‐PCa effects in vitro 228 .…”

“…225 In recent years, the combination of 20(S)-protopanaxadiol with 1α,25-dihydroxyvitamin D3 was reported to suppress tumor growth in vivo, with limited or no toxicity. 226,227 Similarly, 20(S)-ginsenoside Rh2 in combination with 1α,25-dihydroxyvitamin D3 exerted additional anti-PCa effects in vitro. 228 To sum up, 20(S)-protopanaxadiol might be a promising agent for the prevention and treatment of PCa without severe toxicity.…”

Vitamin D in Melanoma: Potential Role of Cytochrome P450 Enzymes

“…It is plausible that inhibition of CYP24A1 can prevent the development of melanoma. In other cancer types (e.g., prostate cancer and breast cancer), CYP24A1 or CYP3A4 inhibitors blocked the degradation of active vitamin D 3 and improved the treatment outcomes in preclinical models or clinical studies [105,[134][135][136][137]. Thus, CYP enzymes can be a viable target in the prevention or treatment of melanoma.…”