Effect of 2-methoxiestradiol in the citotoxicity and chemorresistance of human melanoma cell lines

Abstract

Melanomas are the deadliest form of skin cancer and, despite the low incidence, they represent 80% of the deaths from this type of tumor. The development of specific inhibitors to the mutant form of the onco-protein BRAF has put melanoma among the tumors benefiting from this compound, following the tendency of treatments that exploit the principle of molecular targeted therapy. However, melanoma genetic origin is heterogeneous and they present high chemoresistance, for this reason the search for new strategies for effective treatment is highly motivated, especially because the current therapies lead to selection of resistant cells and resistance after long-term treatment, and tumor recurrence is readily observed. Autophagy is one of the mechanisms involved in chemoresistance, and its role in the treatment of melanoma and other tumors have been showing effective results by reducing chemoresistance. 2-methoxyestradiol (2-ME) is a compound that has anti-proliferative and pro-apoptotic effects in several tumor types, including melanoma, and its effect in autophagic process has been discussed, but not effectively in melanoma. Thus, it is proposed that 2-ME is used in human melanoma cell lines with different mutations and, in particular, in the subgroups with BRAF/N-RAS mutations. Furthermore, it is proposed to verify the effect of 2-ME in synergy with PLX4032, treatment that targets specifically cell lines with B-RAF mutation. Given the increasing importance that the autophagic process has shown, it is focus of the present work to verify the effect of 2-ME in the induction of autophagy in this model. Finally, the efficiency of this compound as adjuvant of PLX4032 will be verified, or its potential as an alternative treatment for melanomas, and its role in autophagy induction in this type of tumor. (AU)