Autophagy and cell death to target cancer cells: exploiting synthetic lethality as cancer therapies.

Since 1940 chemotherapy has been one of the major therapies used to kill cancer cells. However, conventional standard cytotoxic agents have a low therapeutic index and often show toxicity in healthy cells. Over the past decade, progress in molecular biology and genomics has identified signaling pathways and mutations driving different types of cancer. Genetic and epigenetic alterations that characterize tumor cells have been used in the development of targeted therapy, a very active area of cancer research. Moreover, identification of synthetic lethal interactions between two altered genes in cancer cells shows much promise to target specifically tumor cells. For a long time, apoptosis was considered the principal mechanism by which cells die from chemotherapeutic agents. Autophagy, necroptosis (a programmed cell death mechanism of necrosis), and lysosomal-mediated cell death significantly improve our understanding of how malignancy can be targeted by anticancer treatments. Autophagy is a highly regulated process by which misfolded proteins and organelles reach lysosomes for their degradation. Alterations in this cellular process have been observed in several pathological conditions, including cancer. The role of autophagy in cancer raised a paradox wherein it can act as a tumor suppressor at early stage of tumor development but can also be used by cancer cells as cytoprotection to promote survival in established tumors. It is interesting that autophagy can be targeted by anticancer agents to provoke cancer cell death. This review focuses on the role of autophagy in cancer cells and its potential to therapeutically kill cancer cells.