Research Supervisor: Dr. Emma Guns
Title of Presentation: Calcitriol Sensitizes Prostate Cancer cells to PPD Mediated anticancer Activity in Vitro: Pharmacodynamic Based Interaction
Abstract
Background: The potential role of vitamin D metabolites (calcitriol) and ginseng extracts (PPD) in prevention/treatment of many cancers has gained much attention in recent years including prostate cancer (PCa). We evaluated the anticancer activity of calcitriol, PPD, and their combinations on two well characterized human PCa celllines (androgen dependent LNCaP and androgen independent C4-2).Methods: The effects of the treatments on PCa cell viability and proliferation rate were evaluated by MTS and Brdu assays, respectively. We first calculated and compared the IC20, IC50 and IC80 of PPD treated alone and in a combination with 10 nM the clinically relevant concentration of calcitriol. Then, we determined the potential Pharmacodynamic interaction mechanisms as follows: The protein expression levels of the genes those are known to control cell cycle (cyclin D1 and cdk2); apoptosis (Bcl-2, Bax, and Capspases 3), androgen receptor, PSA and vitamin D receptors were examined upon combinational treatment.
Results: Growth inhibition of PCa cells by PPD was further enhanced by the combination with calcitriol in C4-2 and LNCaP cells in FBS containing media. PPD treatment alone inhibited LNCaP and C4-2 cell growth with an IC50 of 53 and 41 µM, respectively. However, in combination treatment the IC50 were significantly reduced to 16 and 23 µM, respectively. The greatest enhancement of inhibition occurred using smaller concentrations of the PPD compound in combination with calcitriol. PPD treatment alone inhibited LNCaP and C4-2 cell growth with an IC20 of 17 and 15 µM, respectively. However, the IC20 were significantly reduced to 7.1 and 5 µM, respectively. Adding calcitriol to PPD significantly lower tumor cell proliferation rate with greater inhibition was seen in C4-2 celllines, compared to cells treated with both agents alone. Calcitriol further enhanced PPD ability to induce apoptosis by up-regulating protein levels of pro-apoptotic (Bax and capspases 3) and increased the inhibition of anti-apoptotic (Bcl-2) and cell cycle regulating protein (cyclin D and cdk2).
Conclusions: Calcitriol enhances PCa cell sensitization to PPD anticancer mediated effect by increasing apoptosis, reducing cell proliferation and retarding cell regulation. Our findings suggest that there is potential clinical value in combining PPD with calcitriol for the treatment of human PCa. These results suggest that combined anti-tumor therapy may be very efficacious as could limit calcitriol toxicity by using lower concentrations in combination with aPPD that has independent and distinct anticancer activity that enhance overall treatment efficacy.