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

Grant number: 12/05732-7
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): September 01, 2012
Effective date (End): August 31, 2013
Field of knowledge:Health Sciences - Pharmacy - Medicines Analysis and Control
Principal Investigator:Silvya Stuchi Maria-Engler
Grantee:Renato Ramos Massaro
Supervisor abroad: Keiran Smalley
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Local de pesquisa : University of South Florida (USF), United States  

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)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MASSARO, R. R.; FAIAO-FLORES, F.; REBECCA, V. W.; SANDRI, S.; ALVES-FERNANDES, D. K.; PENNACCHI, P. C.; SMALLEY, K. S. M.; MARIA-ENGLER, S. S. Inhibition of proliferation and invasion in 2D and 3D models by 2-methoxyestradiol in human melanoma cells. PHARMACOLOGICAL RESEARCH, v. 119, p. 242-250, MAR 2017. Web of Science Citations: 8.
REBECCA, VITO W.; MASSARO, RENATO R.; FEDORENKO, INNA V.; SONDAK, VERNON K.; ANDERSON, ALEXANDER R. A.; KIM, EUNJUNG; AMARAVADI, RAVI K.; MARIA-ENGLER, SILVYA S.; MESSINA, JANE L.; GIBNEY, GEOFFREY T.; KUDCHADKAR, RAGINI R.; SMALLEY, KEIRAN S. M. Inhibition of autophagy enhances the effects of the AKT inhibitor MK-2206 when combined with paclitaxel and carboplatin in BRAF wild-type melanoma. PIGMENT CELL & MELANOMA RESEARCH, v. 27, n. 3, p. 465-478, MAY 2014. Web of Science Citations: 27.

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