Modulating the activity of DNA repair proteins to improve chemotherapy effects

• Grant number: 14/04157-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2014
• End date: May 31, 2019
• Field of knowledge: Biological Sciences - Genetics - Mutagenesis
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Carlos Frederico Martins Menck
• Grantee: Alessandra Luiza Pelegrini
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 14/15982-6 - Consequences of repair deficiencies in damaged genome, AP.TEM
• Associated scholarship(s): 16/17121-3 - The role of ERCC1 and XPF in replicative stress and genetic instability, BE.EP.PD

Abstract

Lung carcinoma is currently the leading cause worldwide and in our country of death due to cancer. It is the most lethal and invasive type, with more than one million new cases diagnosed every year. The high mortality rate is due mainly to the difficulty of early diagnosis, the absence of treatments which offer a definitive cure and by development of chemoresistance by tumor cells. The most therapeutic agents act by inducing DNA damage in these cells. However, changes in the genome protection systems may arise, reducing the efficiency of treatment and induced resistance to therapy. Inhibition of DNA repair by pharmacological products has been proposed as one of the most promising strategies designed to improve the effects of anti-cancer agents and reversing resistance.The aim of this project is modulate the expression and activity of proteins involved in DNA repair, ERCC1, XPC and XPF, by interference RNA and the use of a potential XPC inhibitor to improve cytotoxic effect of chemotherapy and resistance reversal in cell model of lung cancer.It is expected that this silencing system, combined with current therapy protocols might increase the sensitivity of tumor cell lines to chemotherapeutic agents, providing important information for the potential clinical use of combination chemotherapy with specific inhibitors and gene silencing by siRNA. (AU)