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.
Highlights
IntroductionProstate cancer (PCa) is the most common male cancer type identified globally [1]
At the end of the treatment period, the addition of calcitriol to achieved with 20(S)-protopanaxadiol (aPPD) led to significantly higher blockade of tumor development compared to aPPD alone (76% by combination vs. 53% by aPPD, p < 0.01)
Our lab has shown that CYP3A4 is responsible for the hepatic metabolism and inactivation of calcitriol and aPPD is a
Summary
Prostate cancer (PCa) is the most common male cancer type identified globally [1]. Though PCa is curable if it is diagnosed and treated early, a significant number of patients progress to a more advanced stage termed as castration-resistant prostate cancer (CRPC) [2,3,4,5,6,7,8]. The currently available treatment options for CRPC are limited and still represent a therapeutic challenge. Since androgens are one of the main driving forces of prostate cancer, other than chemotherapeutic agents such as docetaxel and cabazitaxel, the androgen receptor (AR) and steroid biosynthesizing cytochrome P450 17A1 (CYP17A1) have been
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
