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Melatonin and vitamin D3 increase TGF-beta1 release and induce growth inhibition in breast cancer cell cultures


, : Melatonin and vitamin D3 increase TGF-beta1 release and induce growth inhibition in breast cancer cell cultures. Journal of Surgical Research 110(2): 332-337

Background: Evidence has accumulated that 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) is involved in the regulation of the proliferation of breast tumor cells. For complete tumor suppression high hypercalcemic doses of 1,25-(OH)2D3 are needed. The aim of this study was to assess the effect of combined treatment of 1,25-(OH)2D3 at low doses and melatonin (MEL) on the proliferation of estrogen-responsive rat breast cancer cell line RM4. Materials and methods: RM4 cell proliferation was assessed by (3H)thymidine uptake. The presence of TGF-beta1 in serum-free conditioned medium was determined by inhibition antibody binding assay. Results: In 17-betaE cultured RM4 cells both MEL and 1,25-(OH)2D3 alone and in combination significantly reduced (3H)thymidine incorporation in a dose-related fashion. MEL by itself was ineffective in inhibiting the FCS-cultured RM4 cells, while 1,25-(OH)2D3 strongly inhibited (3H)thymidine incorporation. Meanwhile, MEL increased the sensitivity of the FCS-cultured RM4 cells to 1,25-(OH)2D3 in the combined regimen, from 20- to 100-fold. MEL significantly enhanced the TGF-beta1 secretion from RM4 cells and vitamin D3 increased the TGF-beta1 secretion in a dose-dependent manner, from 2- to 7-fold. Moreover, a further enhancement of the TGF-beta1 release was obtained with the combined treatment, but only for low 1,25-(OH)2D3 concentrations. The addition of monoclonal anti-TGF-beta1 antibody to the medium of RM4 cells exposed to vitamin D3 alone or in combination with MEL increased the (3H)thymidine uptake compared to the correspondent cells cultured without antibody. Conclusions: Our data point to a potential benefit of combination therapy with 1,25-(OH)2D3 and MEL in the treatment of breast cancer and suggest that the growth inhibition could be related, at least in part, to the enhanced TGF-beta1 secretion.

US$29.90

PMID: 12788662


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