Cell Survival and Cell Death at the Intersection of Autophagy and Apoptosis: Implications for Current and Future Cancer Therapeutics.

Autophagy and apoptosis are functionally distinct mechanisms for cytoplasmic and cellular turnover. While these two pathways are distinct, they can also regulate each other, and central components of the apoptosis or autophagy pathway regulate both processes directly. Furthermore, several upstream stress-inducing signaling pathways can influence both autophagy and apoptosis. The crosstalk between autophagy and apoptosis has an integral role in pathological processes, including those related to cancer, homeostasis, and aging. Apoptosis is a form of programmed cell death, tightly regulated by various cellular and biochemical mechanisms, some of which have been the focus of drug discovery efforts targeting cancer therapeutics. Autophagy is a cellular degradation pathway whereby cells recycle macromolecules and organelles to generate energy when subjected to stress. Autophagy can act as either a prodeath or a prosurvival process and is both tissue and microenvironment specific. In this review we describe five groups of proteins that are integral to the apoptosis pathway and discuss their role in regulating autophagy. We highlight several apoptosis-inducing small molecules and biologics that have been developed and advanced into the clinic and discuss their effects on autophagy. For the most part, these apoptosis-inducing compounds appear to elevate autophagy activity. Under certain circumstances autophagy demonstrates cytoprotective functions and is overactivated in response to chemo- or radiotherapy which can lead to drug resistance, representing a clinical obstacle for successful cancer treatment. Thus, targeting the autophagy pathway in combination with apoptosis-inducing compounds may be a promising strategy for cancer therapy.