The influence of the circadian cycle in resistance to cisplatin in cancer cells

Abstract

Currently, cancer is one of the main causes of morbidity and mortality worldwide, with approximately 14 million new cases and 8.2 million cancer related deaths in 2012. This high index of mortality is very affected by the shortage of treatments that provide a definitive cure, or even a longer life span. One of the most used treatments is the chemotherapy with cisplatin, based on the cytotoxicity caused by DNA damage. However, drug resistance is very common, due to alterations on the genes that protect the cells. Among these alterations, we have the well-known master regulator of antioxidant response, NRF2, as a main cause of resistance in some cases. Interestingly, this gene was demonstrated to be under control of the circadian clock, an internal timing mechanism, orchestrating variations in behavior, physiology and metabolism according to daily changes in our environment such as temperature and light/dark cycles. Thus, this project aims to develop cancer cell lines that can be synchronized and followed in their circadian rhythm. We hope these cells will help to understand the role of NRF2 variation on the sensitivity of tumor cells to cisplatin during the different phases of the circadian cycle. This project may contribute to the development of protocols taking in consideration the circadian clock in cancer therapy. (AU)