1α,25-dihydroxyvitamin D
3 [1α,25(OH)
2D
3], the most active form of vitamin D
3, and its analogues have therapeutic benefits for prostate cancer treatment. However, the development of hypercalcemia is an obstacle to clinical applications of 1α,25(OH)
2D
3 for cancer therapy. In this study, we provide evidence that menthol, a key component of peppermint oil, increases an anti-proliferation activity of 1α,25(OH)
2D
3 in LNCaP prostate cancer cells. We found that menthol
per se does not exhibit antiproliferative activity, but it is able to enhance 1α,25(OH)
2D
3-mediated growth inhibition in LNCaP cells. Fluorometric assays using Fura-2 showed that 1α,25(OH)
2D
3 does not induce acute Ca
2+ response, whereas menthol evokes an increase in [Ca
2+]
i, which suggests that cross-talks of menthol-induced Ca
2+ signaling with 1α,25(OH)
2D
3-mediated growth inhibition pathways. In addition, Western blot analysis revealed that 1α,25(OH)
2D
3 and menthol cooperatively modulate the expression of bcl-2 and p21 which provides the insight into the molecular mechanisms underlying the enhanced 1α,25(OH)
2D
3-mediated growth inhibition by menthol. Thus, our findings suggest that menthol may be a useful natural compound to enhance therapeutic effects of 1α,25(OH)
2D
3.
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