Isothiouronium Salts Reduce NRAS Expression, Induce Apoptosis and Decrease Invasion of Melanoma Cells
Fabiola Branco Filippin-Monteiro,
Adailton Joao Bortoluzzi,
Marcus Mandolesi Sa,
Tania Beatriz Creczynski-Pasa.
Melanoma is a very aggressive type of skin cancer. Mutation in BRAF and NRAS are often found in
patients with this disease. Therefore, in recent years the search for new molecules that inhibit these proteins has been
intensified. After many years with no new treatments for melanoma, the U.S. Food and Drug Administration (FDA)
recently approved vemurafenib. However, many patients have already acquired resistance and have experienced severe
side effects. Therefore, this work aims to evaluate a new set of compounds including allylic isothiouronium salts (1, 2
and 3), N-phenyl-substituted analog (4) and isothiosemicarbazide salts (5 and 6) for their potential antimelanoma
activity. To this end, viability assay, cell cycle analysis, expression of NRAS and BRAF, as well as migration and invasion assay were
performed with different melanoma cell lines. Isothiouronium salts 1-3 presented CC50 (concentration required to reduce the cell number
by 50%) in a range of 7-28 μM. Furthermore, salt 1 significantly decreased the expression of NRAS. However, cells incubated with these
salts did not disturb the cell cycle phases; instead, an increase in the number of apoptotic cells was observed. Regarding potential antiinvasion
effects, both 1 and 2 prevented cell migration as well as cell invasion. Finally, when salts 1 and 2 were associated with
vemurafenib, a marked decrease in cell viability was observed when compared to the compounds incubated alone. Briefly, the salts
exhibited interesting results, especially 1, which decreased the expression of NRAS, increased apoptotic cells and, when combined with
vemurafenib, resulted in a synergistic effect. Therefore, we intend to test compound 1 in pre-clinical studies.
Keywords: Anti-invasion activity, antitumoral action, cytotoxicity, expression of NRAS, isothiouronium salts, melanoma cells.
Rights & PermissionsPrintExport