Role of autophagy in cholangiocarcinoma: An autophagy-based treatment strategy

Table 1 Small molecules able to induce autophagic activity

Agents	Mechanism of action
GDC-0941	Inhibitor of class I PI3K
GDC-0980	Dual inhibitor of PI3K and mTORC1
Everolimus	mTORC1 inhibitor
Temsirolimus	mTORC1 inhibitor
Rapamycin	mTORC1 inhibitor
Tat–beclin 1 peptide	Releases beclin-1 into cytoplasm-regulate autophagosome formation
Metformin	AMPK activator
Fluspirilene	Antagonists of L-type Ca2+ channels
Loperamide	Antagonists of L-type Ca2+ channels
Amiodarone	Antagonists of L-type Ca2+ channels
Isoliensinine	Natural alkaloid
Cepharanthine	Natural alkaloid

mTORC1: Mammalian target of rapamycin complex 1; AMPK: 5’ AMP-activated protein kinase; PI3K: Phosphatidylinositol 3-kinases; AKT: Protein kinase B; Beclin-1: The mammalian ortholog of the yeast autophagy-related gene 6 (Atg6).

Table 2 Small molecules able to inhibit autophagic activity

Agents	Mechanism of action
3-Methyladenine (3-MA)	Inhibitor of class III PI3K
LY294002	PI3K inhibitor
Wortmannin	PI3K inhibitor
SB202190	Cross-inhibition of the PI3K/mTOR and MAPKs pathway
MHY1485	Activator of mTOR
Azithromycin	Inhibitor of v-ATPase, inhibition of lysosomal acidification
Bafilomycin A1	Inhibitor of v-ATPase, inhibition of lysosomal acidification
Concanamycin A	Inhibitor of v-ATPase, inhibition of lysosomal acidification
Chloroquine (CQ)	Autophagosome-lysosome fusion
Hydroxy-chloroquine (HCQ)	Autophagosome-lysosome fusion
Clomipramine	Alter acidification of lysosomes
Verteporfin	Alter acidification of lysosomes
Paclitaxel	Microtubule stabilizer- inhibit phosphorylation of VPS34 at T159
Spain-1	Inhibits the activity of ubiquitin-specific peptidases, USP10 and USP13
Monensin	Inhibit autophagosome-lysosome fusion

PI3K: Phosphatidylinositol 3-kinases; mTORC1: Mammalian target of rapamycin complex 1; AMPK: 5’ AMP-activated protein kinase;VPS: Vacuolar protein sorting; ATG: Autophagy-related proteins; USP: Ubiquitin-specific protease.