Application and interpretation of current autophagy inhibitors and activators

Abstract

Autophagy is the major intracellular degradation system, by which cytoplasmic materials are delivered to and degraded in the lysosome. As a quality control mechanism for cytoplasmic proteins and organelles, autophagy plays important roles in a variety of human diseases, including neurodegenerative diseases, cancer, cardiovascular disease, diabetes and infectious and inflammatory diseases. The discovery of ATG genes and the dissection of the signaling pathways involved in regulating autophagy have greatly enriched our knowledge on the occurrence and development of this lysosomal degradation pathway. In addition to its role in degradation, autophagy may also promote a type of programmed cell death that is different from apoptosis, termed type II programmed cell death. Owing to the dual roles of autophagy in cell death and the specificity of diseases, the exact mechanisms of autophagy in various diseases require more investigation. The application of autophagy inhibitors and activators will help us understand the regulation of autophagy in human diseases, and provide insight into the use of autophagy-targeted drugs. In this review, we summarize the latest research on autophagy inhibitors and activators and discuss the possibility of their application in human disease therapy.

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

“…72,178 3-methyladenine (3-MA), first discovered as an autophagy inhibitor, 179 shows functional similarity with LY294002, which may exert dual effects on class I and class III PtdIns3Ks. 178,180 In comparison to 3-MA, which has been shown to have a dual effect on autophagy due to its transient inhibitory effect on class III PtdIns3K, wortmannin is a preferred autophagy inhibitor based on its persistent inhibition of class III PtdIns3K. 181 Nevertheless, caution must be taken when these autophagy inhibitors are used, with nutrient conditions and biological contexts taken into account.…”

Pharmacological inhibition of lysosomes activates the MTORC1 signaling pathway in chondrocytes in an autophagy-independent manner

“…Since both Baf and CQ are widely used for inhibition of autophagy we first tested the hypothesis that blocking of autophagic flux causes the observed phenotype. 8 To address this hypothesis we have created chondrocytespecific Atg5cKO mice and found that genetic ablation of autophagy leads to a slight growth retardation associated with elevated levels of apoptosis and inhibited proliferation. 23 However, no changes in chondrocyte differentiation or hypertrophy could be detected in these mice.…”

“…5 Lysosomal activity can be blocked by pharmacological inhibitors such as bafilomycin A 1 (Baf) which binds at the interface between transmembrane helices 1, 2, and 4 of ATP6V0C/subunit c of the V 0 domain of the v-ATPase, and prevents helical swiveling and, accordingly proton accumulation in the lysosome), chloroquine (CQ, which neutralizes the lysosomal pH by an unknown mechanism), and leupeptin (which inhibits enzymatic activity within lysosomes). [6][7][8] MTORC1 activity is reduced when lysosomal activity is disrupted, presumably by reducing the pool of intra-lysosomal amino acids, and hence disrupting the "inside-out" model. 9 MTORC1 is emerging as a key player in longitudinal bone growth.…”

Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype

“…Repression of Atg5 has been demonstrated to lead to inhibition of autophagy (Yang et al, 2013). To confirm the involvement of autophagy in mediating combination synergy, the effect of silencing Atg5 using two independent siRNA was tested.…”