Impact of the circadian clock on the DNA repair capacity and drug sensitivity of normal and cancer cells: towards chronopersonalized chemotherapy

• Grant number: 15/50080-6
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2016
• End date: March 31, 2019
• Field of knowledge: Biological Sciences - Genetics
• Agreement: Erasmus Universiteit Rotterdam
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Carlos Frederico Martins Menck
• Grantee: Carlos Frederico Martins Menck
• Principal researcher abroad: Gijsbertus Theodorus Johannes van der Horst
• Institution abroad: Erasmus University Rotterdam (EUR), Netherlands
• 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

Abstract

The circadian clock is an internal timing mechanism, orchestrating diurnal variations in behavior, physiology and metabolism, aimed to best prepare us for daily recurring changes in our environment (i,e. the light/dark cycle). Evidence is increasing that uptake, metabolization and detoxification of chemicals is under control of the circadian clock and that, accordingly, the severity of toxic responses can depend on the time-of-day of exposure. Such chronotoxic properties of compounds can be very useful when treating cancer with chemotherapeutic or other anti-cancer agents. Chronomodulated therapy involves protocols in which chemotherapeutic agents are given at a specific moment of the day. The purpose of this project is to make a start with the evaluation of the impact of the circadian system on mechanisms of DNA damage processing (including DNA damage repair and replication of damaged DNAtransletion synthesis), and, as a consequence, the sensitivity of normal and cancer cells to chemotherapeutic compounds_ Ultimately, this knowledge can be used to develop chronomodulated treatment protocols for clinical application (chronopersonalized medicine), aiming at optimizing therapeutic efficacy, and reducing unwanted side effects. (AU)