Executive Summary : | Cancer is one of the most common chronic diseases and is the second leading cause of death worldwide, after cardiovascular disease. It is not a single disease but is a collection of multiple diseases in which the cells become abnormal and divide without control. Because of the high metabolic rate, increased proliferation, and mitochondrial dysfunction, the redox environment of tumor cells is altered as compared to the normal cells. As a result, cancer cells usually have high quantities of Reactive Oxygen Species (ROS), making cells vulnerable to oxidative stress and redox imbalance. The tumor cells also upregulate their antioxidant system to control the increased levels of ROS to preserve the redox status of the cells. Among the antioxidant enzymes, thioredoxin reductase (TrxR) plays key roles in the tumor growth and its progression. Therefore, inducing apoptosis (cell death) in mammalian cells through inhibition of the TrxR by synthetic complexes has been considered as an important strategy in anticancer therapy. However, apoptosis is also the major natural pathway of cell death to control the cell population under physiological conditions. Furthermore, the resistance to apoptosis has been observed in many cases. Recently, ferroptosis, an iron-dependent, non-apoptotic mode of cell death has attracted significant attention. Ferroptosis is distinct both biochemically and morphologically from other forms of cell deaths such as apoptosis, necroptosis, and autophagy. Inducing ferroptosis in cancer cells appears to be an interesting strategy in the development of novel anticancer agents. In this project, we would like to investigate the role of TrxR in ferroptosis in cancer cells and develop stable gold(I)-carbene complexes as inhibitors of the enzyme. A series of gold(I) complexes having different ligand systems will be synthesized and studied for their ability to induce ferroptosis by covalently inhibiting TrxR. The TrxR activity in the presence of gold(I) complexes will be studied using the recombinantly expressed and purified proteins, TrxR and thioredoxin (Trx) and the required cofactor NADPH. The selectivity of the complexes in inducing ferroptosis will be studied using various cancer cells by following appropriate biomarkers of ferroptosis, apoptosis, necrosis and autophagy. These studies would provide insights into the mechanism of ferroptosis by gold(I) complexes and help in developing new anticancer agents. |