Therapeutic Targeting of Autophagy

Abstract

Autophagy is a catabolic process that facilitates nutrient recycling via degradation of damaged organelles and proteins through lysosomal mediated degradation. Alterations in this complex, and tightly regulated process, lead to disease. Autophagy is widely accepted as cytoprotective against neurodegenerative diseases and a variety of clinical interventions are moving forward to increase autophagy as a therapeutic intervention. Autophagy has both positive and negative roles in cancer and this has led to controversy over whether or how autophagy manipulation should be attempted in cancer therapy. Nevertheless, cancer is the disease where most current activity in trying to manipulate autophagy for therapy is taking place and dozens of clinical trials are using autophagy inhibition with Chloroquine or Hydroxychloroquine in combination with other drugs for the treatment of multiple neoplasms. Here, we review recent literature implicating autophagy in neurodegenerative diseases and cancer and highlight some of the opportunities, controversies and potential pitfalls of therapeutically targeting autophagy.

Keywords: Autophagy; Cancer; Clinical trials; Neurodegenerative disease.

Fig. 1

Interventions that target autophagy. Macroautophagy is controlled by nutrient availability via regulation by mTORC1, which under conditions of nutrient availability can inhibit the formation of Ulk1/2 complexes. Ulk complexes facilitate Beclin-1 complex formation and phagaphore initiation. Phagaphore elongation is then mediated by LC3-PE conjugation and ATG5-12 conjugation. Finally, double membrane autophagasomes fuse with lysosomes to form autophagolysosomes resulting in degradation of autophagosome contents by lysosomal hydrolases. A number of pharmacological and naturally occurring agents have been designed/discovered that target this pathway allowing interventions that upregulate and down regulate autophagy.