Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

Abstract

Autophagy plays an essential role in cell survival/death and functioning. Modulation of autophagy has been recognized as a promising therapeutic strategy against diseases/disorders associated with uncontrolled growth or accumulation of biomolecular aggregates, organelles or cells including those caused by cancer, aging, neurodegeneration, and liver diseases such as α1antitrypsin deficiency. Numerous pharmacological agents that enhance or suppress autophagy have been discovered. However, their molecular mechanisms of action are far from clear. Here we collected a set of 225 autophagy modulators and carried out a comprehensive quantitative systems pharmacology (QSP) analysis of their targets using both existing databases and predictions made by our machine learning algorithm. Autophagy modulators include several highly promiscuous drugs (e.g. artenimol and olanzapine acting as activator, fostamatinib as inhibitor, or melatonin as dual-modulator), as well as selected drugs uniquely targeting specific proteins (~30% of modulators). They are mediated by three layers of regulation: (i) pathways involving core autophagy-related (ATG) proteins such as mTOR, AKT, and AMPK; (ii) upstream signaling events that regulates the activity of ATG pathways such as calcium-, cAMP-, and MAPK-signaling pathways; and (iii) transcription factors regulating the expression ATG proteins such as TFEB, TFE3, HIF-1, FoxO, and NF-κB. Our results suggest that PKA serves as a linker bridging between various signal transduction events and autophagy. These new insights contribute to a better assessment of the mechanism of action of autophagy modulators as well as their side effects, development of novel polypharmacological strategies, and identification of drug repurposing opportunities.

Autophagy and Oxidative Balance Mediate the Effect of Carvedilol and Glibenclamide in a Rat Model of Renal Ischemia-Reperfusion Injury

“…Furthermore, the glibenclamide group showed significant increase in H score of Beclin-1 when compared to the IRI group. To support this finding, Shi et al [25] reported that glibenclamide could modulate autophagy and suppress tubular cell apoptosis through downregulation of Beclin-1 gene transcription. Furthermore, the combined group obviously showed significant increase of H score of Beclin-1 when compared with the other groups, which may be attributed to the potent stimulatory effect of autophagy activity of both carvedilol and glibenclamide.…”