Table 2.

Autophagy modulators in clinical trials and their mechanisms of action.

Modulator	Modulation	Mechanism of Action	Reference
HCQ and CQ	Inhibition	Inhibition of lysosomal acidification and thus the blockade of the terminal step of autophagic substrate degradation	(Perez-Hernandez et al., 2019)
Rapamycin (sirolimus) Everolimus Temsirolimus	Activation	mTOR inhibition.	(Mandrioli et al., 2018)
Pantoprazole	Inhibition	Inhibition of H+/K + ATPase proton pumps in membranes of intracellular endosomes and increase of endosomal pH, resulting in inhibition of autophagosome maturation.	(Marino et al., 2010)
Metformin	Activation	Activation of AMPK, a sensor of cellular energy levels (increased AMP/ATP ratio) in the cell	(Novita et al., 2019)
Ricolinostat (ACY-1215)	Inhibition	Selective inhibition of HDAC6, which mediates trafficking of ubiquitinated misfolded proteins to the aggresome/autophagy pathway.	(Vogl et al., 2017)
Vorinostat (suberoylanilide hydroxamic acid; SAHA)	Activation	Pan-HDAC inhibitor; inhibition of mTOR, which results in the dephosphorylation, and thus activation, of the autophagic protein kinase ULK1 and increases LC3 expression.	(Gammoh et al., 2012)
Devimistat (CPI-613)	Inhibition	Inhibition of pyruvate dehydrogenase and ketoglutarate dehydrogenase of TCA cycle, thus impairment of pancreatic cell mitochondrial metabolism.	(Philip et al., 2019)
Spermidine	Activation	Suppression of acetyltransferase activity of EP300, and inducing the acetylation or deacetylation of autophagy-related genes (Atgs).	(Yang et al., 2017)
Bortezomib	Inhibition; activation	Induction of ERK phosphorylation to suppress cathepsin B, thus inhibition of the catalytic process of autophagy; blockade of p62 degradation. Induction of autophagy through endoplasmic reticulum stress.	(Kao et al., 2014) (Li et al., 2018b)
Sorafenib	Activation	Activation of HP1-STAT3-Mcl-1-Beclin1 pathway and releasing Beclin1 from Mcl-1; mTORC1 inhibition; activation of IRE1 signaling pathway of ER stress, thus reduction of ER stress-induced cell death; activation of AMPK.	(Sun et al., 2017)
Colchicine	Activation	Upregulation of proteins involved in autophagy, including the master regulator transcription factor EB (TFEB), the TFEB regulated adaptor protein SQSTM1/p62 and autophagy player microtubule-associated protein 1A/1B-light chain 3 (LC3)	(Mandrioli et al., 2019)
188Re-liposome	Inhibition	Microtubule-associated protein 1 light chain 3B (LC3) and lysosomal proteins, including Lamp-1 and cathepsin-B and p21WAF/Cip1 levels decline. 188Re-liposome is effective in the suppression of stemness markers’ expression.	(Chang et al., 2017)
Trehalose	Inhibition; activation	Inhibition of autophagosome and lysosome fusion. Inhibition of cellular import of glucose and fructose through SLC2A (GLUT) transporters; stimulation of autophagy through AMPK and activation of ULK1.	(Lee et al., 2018) (Mardones et al., 2016)
NAD+ (and its precursors)	Activation	Induction of autophagy/mitophagy	(Bonkowski and Sinclair, 2016)
2-deoxyglucose	Activation	ER stress and unfolded protein response; inhibition of glycolysis.	(Stein et al., 2010)

AMPK, 5′ AMP-activated protein kinase; HDAC, histone deacetylase; TCA cycle, tricarboxylic acid cycle; TFEB, master regulator transcription factor EB; SQSTM1/p62, the TFEB regulated adaptor protein; microtubule-associated protein 1A/1B-light chain 3; ER, endoplasmic reticulum, NAD+, nicotinamide adenine nucleotide.