Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFβ-1-dependent growth inhibition of breast cancer cells

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Published on Wednesday, 19 February 2014

Abstract

Melatonin and vitamin D3 inhibit breast cancer cell growth and induce apoptosis, but they have never been combined as a breast cancer treatment.

Therefore, we investigated whether their association could lead to an enhanced anticancer activity. In MCF-7 breast cancer cells, melatonin together with vitamin D3, induced a synergistic proliferative inhibition, with an almost complete cell growth arrest at 144 hr.

Cell growth blockade is associated to an activation of the TGFβ-1 pathway, leading to increased TGFβ-1, Smad4 and phosphorylated-Smad3 levels.

Concomitantly, melatonin and D3, alone or in combination, caused a significant reduction in Akt phosphorylation and MDM2 values, with a consequent increase of p53/MDM2 ratio. These effects were completely suppressed by adding a monoclonal anti-TGFβ-1 antibody to the culture medium.

Taken together, these results indicate that cytostatic effects triggered by melatonin and D3 are likely related to a complex TGFβ-1-dependent mechanism, involving down-regulation of both MDM2 and Akt-phosphorylation.

 

 

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