Autophagy

Autophinib
1644443-47-9
SBI0206965
1884220-36-3
SMER28
307538-42-7
3BDO
890405-51-3

Background


An overview of autophagy

Just as cells must manufacture necessary components for proper function, so must they break down damaged or unnecessary organelles and other cellular constituents. In order to maintain this balance, the cells employ two primary degradative pathways. The first is the proteasome, which is responsible for the breakdown of most short-lived proteins. The second is autophagy, a process induced by nutrient limitation and cellular stress, which governs the degradation of the majority of long-lived proteins, protein aggregates and whole organelles. It enables cells to survive stress from the external environment, such as nutrient deprivation, as well as internal stresses like accumulation of damaged organelles and pathogen invasion.

Major types of autophagy

Present in all eukaryotic cells, three different types of autophagy can be distinguished: macroautophagy, microautophagy and chaperone-mediated autophagy, and they differ in their mechanisms and functions. Macroautophagy is the most characterized form.

Autophagy-inhibitors

Inhibition of autophagy

Autophagy can be inhibited at several steps by a number of pharmacological drugs and also more recently using siRNAs against specific autophagy proteins. As described by researchers, commonly used pharmacological inhibitors of autophagosome formation are PI3K inhibitors, such as wortmannin, LY290002 and 3-MA. Other drugs, such as okadaic acid and AICAR, an AMPK activator, inhibit autophagy by less well understood mechanisms. Furthermore, the amino acid leucine has been shown to inhibit autophagy when added to starvation medium and to induce autophagy when removed from the growth medium. Drugs that act at a later stage are the microtubule-depolymerizing drugs vinblastine and nocodazole. These inhibit the fusion of autophagosomes with lysosomes and thereby inhibit protein degradation, although both drugs also affect the formation of AVs.

Autophagy and diseases

Dysregulated autophagy is implicated in numerous pathophysiological processes such as neurodegenerative diseases, infectious or metabolic diseases and cancer. In the case of cancer, most of the compounds in the clinic cause cellular stress and activate autophagy after drug treatment in vitro. Even if it was originally proposed that autophagic cell death is part of the mechanism of anticancer drugs, the emerging picture is that the increased autophagy seen during anticancer drug treatment could be a survival response of the dying cells, rather than a cause of cell death.

References:

Pasquier, B. (2016). Autophagy inhibitors. Cellular and molecular life sciences, 73(5), 985-1001.

Deretic, V. (Ed.). (2006). Autophagy in immunity and infection: a novel immune effector. John Wiley & Sons.