Table 2.
Therapeutic benefits of autophagy modulators in diverse human diseases.
| Diseases | Selected autophagy modulators | Mechanisms of autophagy modulation | Therapeutic benefits in animal and iPSC models |
|---|---|---|---|
| Neurodegenerative diseases | Rapamycin, CCI-779 (Inducers) | Inhibition of mTORC1 (Blommaart et al., 1995; Ravikumar et al., 2004) | HD flies (Ravikumar et al., 2004; Sarkar et al., 2008), FTD flies (Berger et al., 2006), HD mice (Ravikumar et al., 2004), AD mice (Spilman et al., 2010), FTD mice (Wang et al., 2012; Ozcelik et al., 2013; Jiang et al., 2014), SCA3 mice (Menzies et al., 2010), Prion disease mice (Cortes et al., 2012) |
| Lithium (Inducer) | Reduction of inositol and IP3; mTORC1-independent (Sarkar et al., 2005) | HD flies (Sarkar et al., 2008), AD mice (Zhang et al., 2011), FTD mice (Shimada et al., 2012), ALS mice (Fornai et al., 2008) | |
| Carbamazepine (Inducer) | Reduction of inositol and IP3; mTORC1-independent (Sarkar et al., 2005) | AD mice (Li et al., 2013), FTD mice (Wang et al., 2012), ALS mice (Zhang et al., 2018), NPC1 patient iPSC-derived neurons (Maetzel et al., 2014) | |
| Trehalose (Inducer) | mTORC1-independent (Sarkar et al., 2007a); Inhibition of SLC2A and activation of AMPK (DeBosch et al., 2016) | HD mice (Tanaka et al., 2004), AD mice (Du et al., 2013), PD mice (Tanji et al., 2015), FTD mice (Rodriguez-Navarro et al., 2010; Schaeffer et al., 2012), SCA17 mice (Chen et al., 2015), ALS mice (Castillo et al., 2013; Zhang et al., 2014), NPC1 patient iPSC-derived neurons (Maetzel et al., 2014) | |
| Rilmenidine, Clonidine (Inducers) | Reduction of cAMP; mTORC1 independent (Williams et al., 2008) | HD mice (Rose et al., 2010), HD zebrafish (Williams et al., 2008), HD flies (Williams et al., 2008) | |
| Verapamil (Inducer) | Reduction of Ca2+; mTORC1 independent (Williams et al., 2008) | HD zebrafish (Williams et al., 2008), HD flies (Williams et al., 2008), NPC1 patient iPSC-derived neurons (Maetzel et al., 2014) | |
| SMER28 (Inducer) | Mechanism unknown; mTORC1 independent (Sarkar et al., 2007b) | HD flies (Sarkar et al., 2007b) | |
| BRD5631 (Inducer) | Mechanism unknown; mTORC1 independent (Kuo et al., 2015) | NPC1 patient iPSC-derived neurons (Kuo et al., 2015) | |
| Metformin (Inducer) | Activation of AMPK (Buzzai et al., 2007) | HD mice (Ma et al., 2007), LD mice (Berthier et al., 2016) | |
| 6-Bio (Inducer) | Inhibition of mTORC1 signaling (Suresh et al., 2017) | PD mice (Suresh et al., 2017) | |
| AUTEN-67, AUTEN-99 (Inducers) | Inhibition of MTMR14 (Papp et al., 2016; Kovacs et al., 2017) | HD flies (Billes et al., 2016; Papp et al., 2016; Kovacs et al., 2017), PD flies (Kovacs et al., 2017) | |
| Cancer | Chloroquine, Hydroxychloroquine (Blockers) | Mechanism unknown; Impairment of lysosomal acidification and autophagosome-lysosome fusion (Murakami et al., 1998; Boya et al., 2005) | Myc/p53ERTAM induced lymphoma mice (Amaravadi et al., 2007), mice bearing MCF7-RR and LCC9 ER+ breast cancer xenografts (Cook et al., 2014) |
| Lys05, ROC-325 (Blockers) | Mechanism unknown; Impairment of lysosomal acidification and autophagosome-lysosome fusion (McAfee et al., 2012; Carew et al., 2017) | Mice bearing c8161 melanoma, 1205Lu melanoma and HT-29 colon cancer xenografts (McAfee et al., 2012), mice bearing 786-0 RCC xenografts (Carew et al., 2017) | |
| NSC185058, UAMC-2526 (Inhibitors) | Inhibition of ATG4B (Akin et al., 2014; Kurdi et al., 2017) | Mice bearing Saos-2 osteosarcoma xenograft (Akin et al., 2014), Mice bearing HT29 colorectal tumor xenograft (Kurdi et al., 2017) | |
| Pyrvinium pamoate (Inhibitor) | Mechanism unknown; Reduction in Atg gene expression; mTORC1 independent (Deng et al., 2013) | Mice bearing 4TI mammary carcinoma xenograft (Deng et al., 2013) | |
| Torin 1 (Inducer) | ATP-competitive inhibition of mTORC1 (Thoreen et al., 2009) | Mice bearing Tu12 and Tu22 colon cancer xenografts (Francipane and Lagasse, 2013) | |
| Infectious diseases | Tat-Beclin 1 (Inducer) | Interaction with the negative autophagy regulator GAPR-1 (Shoji-Kawata et al., 2013) | Mice infected with chikungunya or West Nile virus (Shoji-Kawata et al., 2013), murine or human macrophages infected with L. monocytogenes bacteria and HIV (Shoji-Kawata et al., 2013) |
| Vitamin D3 (Inducer) | Increase in Beclin 1 (Wang et al., 2008); Increase in Atg gene expression (Yuk et al., 2009) | Human macrophages infected with M. tuberculosis bacteria or HIV or coinfection (Yuk et al., 2009; Campbell and Spector, 2011, 2012) | |
| Carbamazepine (Inducer) | Reduction of inositol and IP3; mTORC1-independent (Sarkar et al., 2005) | Human macrophages infected with M. tuberculosis bacteria or coinfection with HIV (Schiebler et al., 2015), mice infected with multidrug-resistant M. tuberculosis bacteria (Schiebler et al., 2015) | |
| Trehalose (Inducer) | mTORC1-independent (Sarkar et al., 2007a); PI(3,5)P2 agonist, activation of TRPML1 Ca2+ channel (Sharma et al., 2017) | Human macrophages infected with M. tuberculosis bacteria or coinfection with HIV (Sharma et al., 2017), PBMCs from HIV patients (Sharma et al., 2017) | |
| Flubendazole (Inducer) | mTORC1 inactivation; nuclear translocation of TFEB (Chauhan et al., 2015) | Human dendritic cells infected with HIV, and HeLa cells infected with E. coli bacteria (Chauhan et al., 2015) | |
| Nitazoxanide (Inducer) | Inhibition of mTORC1 signaling (Lam et al., 2012) | Human acute monocytic leukemia cells or PBMCs infected with M. tuberculosis bacteria (Lam et al., 2012) | |
| Nortriptyline (Inducer) | Mechanism unknown | Human macrophages infected with M. tuberculosis bacteria (Sundaramurthy et al., 2013) | |
| Liver Disease | Carbamazepine (Inducer) | Reduction of inositol and IP3; mTORC1-independent (Sarkar et al., 2005) | AATD mice (Hidvegi et al., 2010), NAFLD and AFLD mice (Lin et al., 2013), FSD patients (Puls et al., 2013), AATD patient iPSC-derived hepatic cells (Choi et al., 2013), NPC1 patient iPSC-derived hepatic cells (Maetzel et al., 2014) |
| Lithium, Valproic acid (Inducers) | Reduction of inositol and IP3; mTORC1-independent (Sarkar et al., 2005) | AATD patient iPSC-derived hepatic cells (Choi et al., 2013) | |
| Trehalose (Inducer) | mTORC1-independent (Sarkar et al., 2007a); Inhibition of SLC2A and activation of AMPK (DeBosch et al., 2016) | NAFLD mice (DeBosch et al., 2016) | |
| Rapamycin (Inducer) | Inhibition of mTORC1 (Blommaart et al., 1995) | NAFLD mice (Lin et al., 2013), NPC1 patient iPSC-derived hepatic cells (Maetzel et al., 2014) | |
| Myopathies | Rapamycin, CCI-779 (Inducers) | Inhibition of mTORC1 (Blommaart et al., 1995; Ravikumar et al., 2004) | Collagen type VI muscular dystrophy mice (Grumati et al., 2010), LMNA cardiomyopathy mice (Choi et al., 2012; Ramos et al., 2012) |
| AICAR (Inducer) | Activation of AMPK (Buzzai et al., 2007) | DMD mice (Pauly et al., 2012) | |
| Simvastatin (Inducer) | Inhibition of Rac1-mTOR pathway (Wei et al., 2013) | DMD mice (Whitehead et al., 2015) | |
| Lifespan extension | Spermidine (Inducer) | Inhibition of histone acetyltransferase and increase in Atg gene expression (Eisenberg et al., 2009) | Flies (Eisenberg et al., 2009), worms (Eisenberg et al., 2009), mice (Eisenberg et al., 2016) |
| Resveratrol (Inducer) | Activation of SIRT1 (Morselli et al., 2010) | Flies (Wood et al., 2004), worms (Wood et al., 2004; Morselli et al., 2010), mice (Baur et al., 2006) | |
| Rapamycin (Inducer) | Inhibition of mTORC1 (Blommaart et al., 1995) | Flies (Bjedov et al., 2010), mice (Harrison et al., 2009) |
Autophagy modulators have shown beneficial effects in a number of transgenic disease models, such as but not limited to, neurodegenerative disorders, cancer, infectious diseases, liver diseases and myopathies as well as in lifespan extension. Selected examples of autophagy modulators are highlighted in specific pathological contexts. AATD, α1 antitrypsin deficiency; AD, Alzheimer’s disease; AFLD, Alcoholic fatty liver disease; ALS, Amyotrophic lateral sclerosis; AMPK, 5′ adenosine monophosphate-activated protein kinase; Atg, Autophagy-related genes; cAMP, 3′,5′-cyclic adenosine monophosphate; DMD, Duchenne muscular dystrophy; FSD, Fibrinogen storage disease, FTD, Frontotemporal dementia; GAPR-1, Golgi-associated plant pathogenesis-related protein 1; HD, Huntington’s disease; HIV, Human immunodeficiency virus; IP3, Inositol 1,4,5-trisphosphate; iPSC, Induced pluripotent stem cells; LD, Lafora disease; LMNA, Lamin A/C gene; MTMR14, Myotubularin related protein 14; mTORC1, Mechanistic target of rapamycin complex 1; NAFLD, Non-alcoholic fatty liver disease; NPC1, Niemann-Pick type C1 disease; PBMC, Peripheral blood mononuclear cells; PD, Parkinson’s disease; PI(3,5)P2, Phosphatidylinositol 3,5-bisphosphate; RCC, Renal cell carcinoma; SCA, Spinocerebellar ataxia; SIRT1 Sirtuin 1; SLC2A, Solute carrier 2A; TRPML1, Transient receptor potential cation channel mucolipin subfamily member 1.