Vitamina D3: Potencial modulador sobre a Mutagenicidade e a Carcinogenicidade induzida por Doxorrubicina em Drosophila melanogaster e sinergismo com fármacos em sistema in vitro

Abstract

Vitamin D3 (VD3) deficiency favors DNA damage, while supplementation, depending on the dose, can induce pro-oxidant activity, tumors and prevent viral infections. The objectives of this study were to investigate the mutagenic and carcinogenic potential of VD3 alone or in combination with Doxorubicin (DXR) through the Somatic Mutation and Recombination Test (SMART) in wings and the Epithelial Tumor Test (ETT), both in Drosophila melanogaster. In addition, to assess whether synergism occurs between VD3 and the PARP AZD2461 inhibitor and between VD3 and DXR, in the human breast cancer cell line MDA-MB-231. The results revealed that, in Drosophila melanogaster, VD3 alone did not increase the frequency of mutant spots, but reduced the frequency of mutant spots when co-administered with DXR. In addition, VD3 did not alter the recombinogenic effect of DXR in both crosses (ST and HB). VD3 alone did not increase the total frequency of tumor in D. melanogaster, but significantly reduced the total frequency of tumor when co-administered with DXR. The molecular modeling and dynamics between calcitriol and Ecdysone Receptor (EcR) showed a stable interaction, indicating the possibility of signal transduction between VD3 and EcR. The Chou-Talalay method revealed, between the binary combinations VD3 + AZD2461 and VD3 + DXR, additive and synergistic interactions with reduced doses of the compounds and moderate/high effect against the cell line MDA-MB-231 strain of human breast cancer. In conclusion, in the experimental conditions of this investigation and in the biological material tested, VD3 showed modulating effects on the mutagenicity and carcinogenicity induced by DXR in somatic cells of D. melanogaster and exhibited satisfactory interactions with the EcR. In addition, combinations of VD3 with AZD2461 or DXR, potentially synergistic, may represent a promising strategy in the treatment of triple-negative breast cancer.