Role of autophagy associated tumor cell death induced by phenothiazines

• Grant number: 19/25889-7
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2020
• End date: July 31, 2022
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Tiago Rodrigues
• Grantee: Rayssa de Mello Lopes
• Host Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil

Abstract

Cancer is one of the leading causes of death in the world and its incidence is continually increasing. Although the therapeutic arsenal for cancer treatment has significantly improved in recent decades, several challenges remain in this area, including the unresponsiveness of some tumor types, resistance against the currently available drugs, besides the high toxicity to normal cells. Thus, advancing knowledge of tumor biology at the molecular level and, based on this, developing new therapeutic strategies to improve antitumor chemotherapy is an important goal in cancer research. Macroautophagy (hereafter referred to autophagy) is a pathway of lysosomal protein degradation that contributes to the elimination of damaged organelles and recycling of intracellular components under physiological conditions. Autophagy has attracted attention in cancer-related research, since it may act as a pro-survival mechanism to protect tumor cells from various forms of cell stress, although it can also act contributing to apoptotic cell death. As a result, the modulation of autophagy as a strategy to increase the sensitivity of tumor cells to chemotherapy is an approach that has been studied currently. Our research group has been studying the potent cytotoxic effects of phenothiazines on tumor cells for years, and recent data suggest that the modulation of autophagy by these drugs is involved with tumor cell death, but the mechanisms are not fully understood. Thus, in this project the cytotoxic effect of clinically used phenothiazines will be characterized in a panel of leukemic tumor cells of different types and changes in autophagic pathways, as well as the effect of autophagy inducers and inhibitors on cytotoxicity induced by phenothiazines will be studied. The results will contribute to the understanding of the role of autophagy in survival and death in different types of leukemia, as well as to the evaluation of autophagy modulation as a possible therapeutic target for chemotherapy. (AU)