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Menthol Enhances an Antiproliferative Activity of 1alpha,25-Dihydroxyvitamin D(3) in LNCaP Cells.

Park EJ, Kim SH, Kim BJ, Kim SY, So I, Jeon JH - J Clin Biochem Nutr (2009)

Bottom Line: We found that menthol per se does not exhibit antiproliferative activity, but it is able to enhance 1alpha,25(OH)(2)D(3)-mediated growth inhibition in LNCaP cells.Fluorometric assays using Fura-2 showed that 1alpha,25(OH)(2)D(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 1alpha,25(OH)(2)D(3)-mediated growth inhibition pathways.Thus, our findings suggest that menthol may be a useful natural compound to enhance therapeutic effects of 1alpha,25(OH)(2)D(3).

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul 110-799, Korea.

ABSTRACT
1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(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 1alpha,25(OH)(2)D(3) for cancer therapy. In this study, we provide evidence that menthol, a key component of peppermint oil, increases an anti-proliferation activity of 1alpha,25(OH)(2)D(3) in LNCaP prostate cancer cells. We found that menthol per se does not exhibit antiproliferative activity, but it is able to enhance 1alpha,25(OH)(2)D(3)-mediated growth inhibition in LNCaP cells. Fluorometric assays using Fura-2 showed that 1alpha,25(OH)(2)D(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 1alpha,25(OH)(2)D(3)-mediated growth inhibition pathways. In addition, Western blot analysis revealed that 1alpha,25(OH)(2)D(3) and menthol cooperatively modulate the expression of bcl-2 and p21 which provides the insight into the molecular mechanisms underlying the enhanced 1alpha,25(OH)(2)D(3)-mediated growth inhibition by menthol. Thus, our findings suggest that menthol may be a useful natural compound to enhance therapeutic effects of 1alpha,25(OH)(2)D(3).

No MeSH data available.


Related in: MedlinePlus

Antiproliferation effect of 1α,25(OH)2D3 and menthol in LNCaP cells. (A–C) Dose-response effect. The cells were cultured with menthol alone (A), 1α,25(OH)2D3 at 10−4 mM plus menthol at the indicated concentrations (B), or menthol at 0.8 mM plus 1α,25(OH)2D3 at the indicated concentrations (C) for 72 h prior to MTT assays. (D) Time-dependent effect. Cell growth is expressed as a relative value to that of the untreated cells or that of cells harvested at zero time. NC, negative control (ethanol as a vehicle); M, menthol; V, 1α,25(OH)2D3; M+V, menthol plus 1α,25(OH)2D3. The figures show mean ± SD (n = 3-6). *p<0.05, **p<0.01, ***p<0.005.
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Figure 1: Antiproliferation effect of 1α,25(OH)2D3 and menthol in LNCaP cells. (A–C) Dose-response effect. The cells were cultured with menthol alone (A), 1α,25(OH)2D3 at 10−4 mM plus menthol at the indicated concentrations (B), or menthol at 0.8 mM plus 1α,25(OH)2D3 at the indicated concentrations (C) for 72 h prior to MTT assays. (D) Time-dependent effect. Cell growth is expressed as a relative value to that of the untreated cells or that of cells harvested at zero time. NC, negative control (ethanol as a vehicle); M, menthol; V, 1α,25(OH)2D3; M+V, menthol plus 1α,25(OH)2D3. The figures show mean ± SD (n = 3-6). *p<0.05, **p<0.01, ***p<0.005.

Mentions: To assess the antiproliferation activity of menthol, we performed MTT assays using LNCaP cells. Cell growth was gradually decreased depending on menthol concentration (Fig. 1A). At high menthol concentrations above 1.6 mM, the cells began to detach from the culture dish. Although only a few cells were detached immediately after treatment with menthol at 0.8 mM, overall cell growth was not significantly reduced (Fig. 1A). The antiproliferative or cytotoxic effect of menthol was evident only in the presence of the supramillimolar concentration ranges, which indicates that menthol per se has little antitumor activity. We then investigated whether menthol can increase an antiproliferative activity of 1α,25(OH)2D3 in LNCaP cells. The combination of 1α,25(OH)2D3 with menthol above 0.8 mM suppressed significantly cell growth, compared to 1α,25(OH)2D3 alone (Fig. 1B). Dose-response relationship study confirmed that menthol markedly enhances an antiproliferative activity of 1α,25(OH)2D3 (Fig. 1C). These results were further corroborated by quantitating cell growth over time (Fig. 1D). While 1α,25(OH)2D3 alone attenuated cell growth, 1α,25(OH)2D3 combined with menthol almost completely inhibited the growth. Under the conditions, the considerable cell death, as examined by LDH release assay, did not occur and little apparent morphological changes were observed (data not shown).


Menthol Enhances an Antiproliferative Activity of 1alpha,25-Dihydroxyvitamin D(3) in LNCaP Cells.

Park EJ, Kim SH, Kim BJ, Kim SY, So I, Jeon JH - J Clin Biochem Nutr (2009)

Antiproliferation effect of 1α,25(OH)2D3 and menthol in LNCaP cells. (A–C) Dose-response effect. The cells were cultured with menthol alone (A), 1α,25(OH)2D3 at 10−4 mM plus menthol at the indicated concentrations (B), or menthol at 0.8 mM plus 1α,25(OH)2D3 at the indicated concentrations (C) for 72 h prior to MTT assays. (D) Time-dependent effect. Cell growth is expressed as a relative value to that of the untreated cells or that of cells harvested at zero time. NC, negative control (ethanol as a vehicle); M, menthol; V, 1α,25(OH)2D3; M+V, menthol plus 1α,25(OH)2D3. The figures show mean ± SD (n = 3-6). *p<0.05, **p<0.01, ***p<0.005.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: Antiproliferation effect of 1α,25(OH)2D3 and menthol in LNCaP cells. (A–C) Dose-response effect. The cells were cultured with menthol alone (A), 1α,25(OH)2D3 at 10−4 mM plus menthol at the indicated concentrations (B), or menthol at 0.8 mM plus 1α,25(OH)2D3 at the indicated concentrations (C) for 72 h prior to MTT assays. (D) Time-dependent effect. Cell growth is expressed as a relative value to that of the untreated cells or that of cells harvested at zero time. NC, negative control (ethanol as a vehicle); M, menthol; V, 1α,25(OH)2D3; M+V, menthol plus 1α,25(OH)2D3. The figures show mean ± SD (n = 3-6). *p<0.05, **p<0.01, ***p<0.005.
Mentions: To assess the antiproliferation activity of menthol, we performed MTT assays using LNCaP cells. Cell growth was gradually decreased depending on menthol concentration (Fig. 1A). At high menthol concentrations above 1.6 mM, the cells began to detach from the culture dish. Although only a few cells were detached immediately after treatment with menthol at 0.8 mM, overall cell growth was not significantly reduced (Fig. 1A). The antiproliferative or cytotoxic effect of menthol was evident only in the presence of the supramillimolar concentration ranges, which indicates that menthol per se has little antitumor activity. We then investigated whether menthol can increase an antiproliferative activity of 1α,25(OH)2D3 in LNCaP cells. The combination of 1α,25(OH)2D3 with menthol above 0.8 mM suppressed significantly cell growth, compared to 1α,25(OH)2D3 alone (Fig. 1B). Dose-response relationship study confirmed that menthol markedly enhances an antiproliferative activity of 1α,25(OH)2D3 (Fig. 1C). These results were further corroborated by quantitating cell growth over time (Fig. 1D). While 1α,25(OH)2D3 alone attenuated cell growth, 1α,25(OH)2D3 combined with menthol almost completely inhibited the growth. Under the conditions, the considerable cell death, as examined by LDH release assay, did not occur and little apparent morphological changes were observed (data not shown).

Bottom Line: We found that menthol per se does not exhibit antiproliferative activity, but it is able to enhance 1alpha,25(OH)(2)D(3)-mediated growth inhibition in LNCaP cells.Fluorometric assays using Fura-2 showed that 1alpha,25(OH)(2)D(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 1alpha,25(OH)(2)D(3)-mediated growth inhibition pathways.Thus, our findings suggest that menthol may be a useful natural compound to enhance therapeutic effects of 1alpha,25(OH)(2)D(3).

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul 110-799, Korea.

ABSTRACT
1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(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 1alpha,25(OH)(2)D(3) for cancer therapy. In this study, we provide evidence that menthol, a key component of peppermint oil, increases an anti-proliferation activity of 1alpha,25(OH)(2)D(3) in LNCaP prostate cancer cells. We found that menthol per se does not exhibit antiproliferative activity, but it is able to enhance 1alpha,25(OH)(2)D(3)-mediated growth inhibition in LNCaP cells. Fluorometric assays using Fura-2 showed that 1alpha,25(OH)(2)D(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 1alpha,25(OH)(2)D(3)-mediated growth inhibition pathways. In addition, Western blot analysis revealed that 1alpha,25(OH)(2)D(3) and menthol cooperatively modulate the expression of bcl-2 and p21 which provides the insight into the molecular mechanisms underlying the enhanced 1alpha,25(OH)(2)D(3)-mediated growth inhibition by menthol. Thus, our findings suggest that menthol may be a useful natural compound to enhance therapeutic effects of 1alpha,25(OH)(2)D(3).

No MeSH data available.


Related in: MedlinePlus