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

J Pineal Res. 2011 Mar;50(2):150-8. doi: 10.1111/j.1600-079X.2010.00824.x. Epub 2010 Nov 22.


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.

MeSH terms

  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cholecalciferol / pharmacology*
  • Drug Synergism
  • Humans
  • Melatonin / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Transforming Growth Factor beta1 / metabolism*


  • Transforming Growth Factor beta1
  • Cholecalciferol
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Proto-Oncogene Proteins c-akt
  • Melatonin