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Expression of apoptotic markers in melanoma resistant strains Vemurafenib against analogous compound curcumin DM-1

Grant number: 14/09788-2
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): July 01, 2014
Effective date (End): June 30, 2015
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal Investigator:Silvya Stuchi Maria-Engler
Grantee:Gustavo Takashi Ikeda
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

In view of the present skin cancers, melanoma is the least common type (4 %) in the population, however, it is the major cause of mortality, as it is potentially invasive and metastatic. It is a complex disease because it has a huge variety of genetic origins (mutations). Thus, understanding the molecular mechanisms of melanoma becomes crucial for the improvement of therapeutic interventions. There are many points related to genetic transformations, however the most recurrent (90 %) is the changing of the amino acid at position 600 of the BRAF (exchange of valine for glutamic acid), generating the mutated BRAF protein (BRAFV600E). The V600E mutation in BRAF protein, which is a component of the MAPK pathway, acts in a constitutive activation of this pathway. Therefore, understanding the components of this pathway and the elucidation of new mechanisms are important for the development of new anticancer agents. The agent Vemurafenib (PLX4032) is a drug approved by the FDA in 2011, with the potential to inhibit the kinase domain of the BRAFV600E mutation and the MAPK pathway, thereby undermining the development and progression of the disease. Despite the good results obtained with this agent, patients usually present resistance after 3-6 months of treatment, leading to activation of other downstream signaling pathways such as MAPK-dependent pathways (secondary mutations in NRAS and MEK) as well as MAPK-independent (activation of the PI3K-AKT-mTOR pathway), among others. Incidence of chemoresistance has been driving the research for new therapies; among them, combination treatment, such as Dabrafenibe (BRAFV600E inhibitor) and Trametinibe (MEK inhibitor) together, has shown much more outstanding results if compared to individual tests, proving the efficacy of combinatorial therapies protocols. Moreover, the search for antitumor agents which are restricted to tumor tissues without adverse effects is another branch of research that has drawn attention. The compound DM -1 (sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate), an analogue of curcumin, presents such biological characteristics; interestingly, at low concentrations, its antitumor activity is potentially effective. The compound DM-1 acts as an antitumor, antiproliferative and pro-apoptotic agent, both in monotherapy, as well as in combination with other chemotherapeutic agents, increasing the efficacy of treatment and reducing side effects. Thus, the association of various antitumor agents has proven to be an alternative to overcome chemoresistance of melanoma.