Table 1.

Pharmacological activators and inhibitors of autophagy. (*) Nutraceuticals able to modulate autophagy

Pharmacological agent	Chemical structure	Source	Autophagy-associated targets	Mechanism of action	References
Activators
Rapamycin (Sirolimus)	Macrocyclic lactone	Streptomyces hygroscopicus	mTOR	Inhibits mTORC1 (acute and chronic exposure) Inhibits mTORC2 (chronic exposure) Rapamycin binds FKBP12 and act as an allosteric inhibitor	(148)
Temsirolimus	Derivative of rapamycin	Synthetic analog of rapamycin			(149)
Everolimus (RAD-001)	Derivative of rapamycin	Synthetic analog of rapamycin			(150)
Erlotinib	Quinazolinamine	Synthetic compound	EGFR	Inhibition of the EGFR signaling by interaction with ATP binding site	(151)
Imatinib	2-phenyl amino pyrimidine	Synthetic drug	BCR-ABL c-Abl Abl-related gene	Inhibits selectively tyrosine kinases Sequestering of the Bcr-Abl protein into autophagosomes	(152,153)
Dasatinib (BMS-354825)	Derivative of aminopyrimidine	Synthetic compound	Src/Abl family kinases	Reduces the phosphorylation of AKT, mTOR, p70S6K, and S6 kinase expression Requires BECN1 and ATG12	(154,155)
Vorinostat (SAHA)	Hydroxamic acid derivative	Synthetic compound	HDAC	Acetylation of ATG proteins leading to hyperactivation of PIK3C3 Upregulation of LC3 Inhibition of mTOR	(156-158)
Arsenic Trioxide	Amphoteric oxide	Processing of the mineral arsenic	TFEB ROS PI3K/AKT/mTOR	Nuclear translocation of TFEB Inhibition of PI3K/AKT/mTOR pathway Generation of ROS	(159)
Epigallocatechin-3-gallate*	Polyphenol.	Green tea leaves	mTOR-AMPK	Induces activation of AMPK and inhibition of mTOR	(160,161)
Polygonatum cyrtonema lectin*	Lectin	Rhizomes of Polygonatum cyrtonema	Mitochondria-mediated ROS-p38-p53 pathway	Accumulation of mitochondrial ROS, activating p38 and p53	(162,163)
Spermidine*	Polyamine	Dry soy bean, chicken liver, green peas, corn, shell fish, and blue cheese	Acetylation of histones	Modifies epigenetic landscape Increases the expression of ATG	(164,165)
Resveratrol*	Polyphenol	Grapes, apples, plums, blueberries, and peanut	mTOR, AMPK, SIRT1	Inhibiting mTOR via several routes, activates AMPK and SIRT1	(166-168)
Allicin*	Sulfoxide	Allium sativum	p53, mTOR and AMPK	Modulation of the pathways leading to autophagy	(169,170)
Ginsenosides*	Saponins	Ginseng root	Autophagy-related pathways	Modulation of the pathways leading to autophagy	(171,172)
Curcumin*	Diarylheptanoid	Curcuma longa	ROS mTOR	Inhibiition of mTOR Overexpression of autophagy-related proteins	(173-175)
Pharmacological agent	Chemical structure	Source	Molecular target	Mechanism of action	References
Inhibitors
Wortmannin	Furanosteroid	Penicillium funiculosum Talaromyces wortmannii	PI3KC1 (transient) PI3KC3 (persistent)	Inhibition of the production of PIP3	(146)
3-Methyladenin	Adenin	Saccharomyces cerevisiae	PI3KC1 (persistent) PI3KC3 (transient)	Inhibition of PI3K Promotion of autophagic flux under nutrient-rich conditions (dual role)	(176,177)
Chloroquine	Aminoquinoline	Cinchona officinalis	Lysosomal pH SNAP29?	Slows down lysosomal acidification Inhibition of the fusion of autophagosomes with lysosomes	(178,179)
Pepstatin-A	Hexapeptide	Streptomyces sp	Cathepsin D and E	Inhibition of lysosomal proteases Accumulation of LC3-II	(146,180)
Bafilomycin A1	Macrolide	Streptomyces sp	Vacuolar-ATPase SERCA	Reduce lysosomal acidification Disrupt autophagosome-lysosome fusion	(181,182)
Hydroxy-chloroquine	Derivate from chloroquine	Synthetic modification of cloroquine	Lysosomal pH	Slows down lysosomal acidification Inhibition of the fusion of autophagosomes with lysosomes	(183,184)
Spautin-1	4-quinazolinamine	Synthetic compound	Ubiquitin-specific peptidase 10 and 13	Inhibits autophagy by the degradation of PI3K3 and BECN1	(185,186)
SAR405	Pyrimidine	Small molecule inhibitor	Class III PI3K	A selective ATP-competitive inhibitor of PI3K class III	(187)
siRNAs	20 to 24-bp double-stranded RNA	Synthetic compound	ATG mRNA	Knockdown the autophagy machinery, e.g.: ATG5	(188,189)