Study of the contribution of the inhibitory apoptosis protein survivin on effects of prodigiosin and derivatives in melanoma lineages

Abstract

The growing incidence of skin cancer melanoma, as well as your resistance to convencional anticacer therapy, becomes one of the most challenger question in oncology, therefore search for new therapies is constant. The natural marine products are significant source of anticancer compounds. Prodigiosin is a bacterian product, isolated from several species of both gram-negative and gram-positive bacteria, that showed have antiproliferative in diverse tumoral lineages and survivin expression reduction in breast cancer lineages. Survivin is an apoptosis inhibitor, with low expression in normal tissues, although highly expressed in cancerous tissues, besides being related to resistance to chemotherapy. From the prospection of bacteria that produce active compounds in Brazilian coast, our research group isolated four prodiginines: prodigiosin (m/z 324.2059 [M + H]+), ciclononilprodigiosin (m/z 364,2294 [M + H]+), nonilprodigiosin (m/z 366,2453 [M + H]+) and metilciclooctilprodigiosina from a marine microorganisms. Preliminary tests have showed that prodgiosin and its derivatives exhibit selective cytotoxic activity in melanoma lineages as SkMel19 with mutation in BRAFV600E and SkMel147 with mutated NRAS, being more active against Skmel19. The mutated genes in these lineages are essential components of the MAPK pathway, participating of normal processes of growth and survival of cells. The mutation in this pathway leads to its constitutive activation causing exacerbated proliferation. This job aims to test the effects of prodiginines in melanomas lineages muted in BRAF/NRAS gene and by the surviving knockdown by sIRNA. For this it will be done citotoxity assays and it will be analyzed if there is modulation caused by prodigiosin and derivatives in the expression of genes of MAPK pathway and survivin in the melanoma lineages. (AU)