Table IV.

The clinical prospects of autophagy activators and inhibitors.

Drugs	Diseases	Functions	Possible mechanism	In human/animal/cell model	Reference
Autophagy activators
Rapamycin	Breast cancer	Inhibits proliferation of the endoplasmic reticulum-positive MCF-7 cell line	Rapidly stimulate mTOR non-specifically after medium replacement	MCF-7 breast cancer cell line	Chang et al. (2007)
	Transplanted tumors	Inhibits tumor growth at any stage of development	–	–	Eng et al. (1984)
	Pancreatic cancer	Regulates cell growth and cyclin D1 expression	Constitutively actives FRAP-p70s6K pathway and inhibits cyclin D1 expression	MiaPaCa-2 and Panc-1 human pancreatic cancer cells and a pancreatic cancer tissue sample	Grewe et al. (1999)
	Vascular disease	Reduces vascular inflammation	Suppresses macrophage proliferation	Mice	Boada et al. (2020)
	Type 2 diabetes	Improves insulin resistance and hepatic steatosis	Enhances autophagy by the inhibition of mTOR pathway	T2DM rats	Zhou and Ye (2018)
	Myotrophic lateral sclerosis	Reduces neuronal loss and TDP43 inclusions; expands regulatory T lymphocytes with slow progression in ALS patients	Activates autophagy	Four human NB cell lines (AS, NGP, BE2, and KCNR); mice carrying xenograft NB tumors	Mandrioli et al. (2018)
	Facial angiofibromas	Appears effective and safe for treatment of TSC-related facial angiofibromas	–	TB3 cells	Koenig et al. (2018)
		Improves ovarian function and reproductive longevity	–	–	Hine (2017)
Perifosine	Neuroblastoma	increases apoptosis and inhibits neuroblastoma tumor cell growth in vitro and in vivo	Decreases AKT phosphorylation	Four human NB cell lines (AS, NGP, BE2, and KCNR); mice carrying xenograft NB tumors	Li et al. (2010)
	Neuroblastoma	Attenuates brain-derived neurotrophic factor/TrkB-induced chemoresistance	Inhibits AKT	TB3 cells	Li et al. (2011)
Metformin	Glioblastoma	Inhibits growth of human glioblastoma cells and enhances therapeutic response	Activates AMPK, Redd1 and inhibits mTOR pathway	Four human glioblastoma cell lines, U87 (ATCC HTB-14), LN18 (ATCC CRL-2610), U251 and SF767	Sesen et al. (2015)
Metformin and Rapamycin	Prostate tumors	Inhibits progression of prostatic intraepithelial neoplasia lesions to adenocarcinomas in the ventral prostate	Down-regulates mTORC1 signaling	HiMyc mice	Saha et al. (2015)
Metformin	Reproductive health, gynecological cancer	Inhibits progression of prostatic intraepithelial neoplasia lesions to adenocarcinomas in the ventral prostate	Upstream activation of AMPK, resulting in inhibition of the mTOR pathway.	HiMyc mice	Saha et al. (2015)
Autophagy inhibitors
Bafilomycin A1	Pediatric B-cell acute lymphoblastic leukemia	Inhibits and kills pediatric B-cell acute lymphoblastic leukemia cells	Targets both autophagy and apoptosis by disassociating the Beclin 1–Vps34 complex	–	Yuan et al. (2015)
	Microcephaly	Inhibits ZIKV entry and prevents the spread of the infection by interfering with viral maturation	Inhibits V-ATPase	–	Sabino et al. (2019)
	Tongue squamous cell carcinoma	Increases the sensitivity of tongue squamous cell carcinoma cells to cisplatin	Inhibition of the lysosomal uptake of platinum ions but not autophagy	–	Chu et al. (2018)
Chloroquine	Breast cancer	Enhances the efficacy of tumor cell killing by combination with chemotherapeutic drugs and radiation	–	–	Maycotte et al. (2012)
	Colon cancer	Enhances the chemotherapeutic activity of 5-fluorouracil in a colon cancer cell line via cell cycle alteration	Anti-cancer effect of 5-FU via cell cycle inhibition	Human colon cancer DLD-1 cells	Choi et al. (2012)
3-MA or chloroquine	Glioblastomas	Improves the efficacy of curcumin/temozolomide combination therapy	Increases apoptosis	C6, U251MG and U87MG cell lines; primary astrocytes	Zanotto-Filho et al. (2015)
	Malignant gliomas	Enhances temozolomide cytotoxicity	Blocks autophagy and triggers endoplasmic reticulum stress, increasing the chemosensitivity of glioma cells to temozolomide	Subcutaneously implanted U87MG tumors from mice	Golden et al. (2014)
	Glioma	Potentiates temozolomide cytotoxicity	Inhibits mitochondrial autophagy	Tumor cells derived from a glioblastoma patient and human U87-MG glioblastoma cells	Hori et al. (2015)
Hydroxy chloroquine	Advanced solid tumors and melanoma	Augments cell death in preclinical models	Blocks autophagy	–	Rangwala et al. (2014a,b)
Lucanthone	Breast cancer	Induces apoptosis via cathepsin D accumulation and enhances vorinostat-mediated cell death in breast cancer models.	Induces lysosomal membrane permeabilization	p53(+/+) and p53(−/−) HCT116 cells	Carew et al. (2011)
Wortmannin	Ovarian cancer	Enhances cisplatin-induced apoptosis	Activates PI3K/Akt signaling pathway	A2780 ovarian adenocarcinoma cell line and A2780cis	Zhao et al. (2014)

3-MA, 3-methylade nine; AKT, protein kinase B; ALS, amyotrophic lateral sclerosis; AMPK, AMP-activated protein kinase; MCF-7 cells, human breast cancer cell lines; mTOR, mammalian target of rapamycin; NB tumor, neuroblastoma; T2DM rat, type 2 diabetes mellitus rat; TrkB, neurotrophic receptor tyrosine kinase 2; TSC, tuberous sclerosis complex; ZIKV, Zika virus.