Table 1.
Main modulators of autophagy available to date and their limitations
| Agent | Mode of action | Blood–brain barrier permeant | Status | Major limitations | Refs |
|---|---|---|---|---|---|
| Activators | |||||
| A-769662 | AMPK activation? | Unknown | In preclinical development | Unclear MOA (requires upstream AMPK-activating kinase) | 130 |
| Antimycobacterial antibiotics | Altered ROS production | Yes | Approved for treatment of mycobacterial infections | Potentially interferes with many ROS-sensitive processes | 178 |
| BECN1-derived peptide | BECN1 activator | Yes | In preclinical development | Limitations associated with chemical nature (shelf stability and potential immunogenicity) | 256 |
| BRD5631 | Unknown | Unknown | In preclinical development | Unclear MOA (independent of mTORC1) | 179 |
| Caloric restriction | Multiple | NA | NA | Potentially dangerous for subjects with weight problems (for example, patients with cachectic cancer); compliance issues | 10,54,118,128,13 1,135,148,150,16 4,180,188,231,237,240 |
| Carbamazepine | Reduction in Ins(1,4,5)P3 and inositol levels | Yes | Approved for treatment of seizures and bipolar disorders | Psychoactive agent, inhibits various neuronal functions | 134,137 |
| Carbon monoxide | Altered ROS production | Yes | Experimental agent | Potentially interferes with many ROS-sensitive processes | 182 |
| Chloramphenicol | Unknown | Yes | Approved for second-line treatment of bacterial infections | Unclear MOA and potentially mitochondriotoxic | 116 |
| Everolimus (also known as RAD-001) | mTORC1 inhibition | Yes | Approved for cancer therapy | Inhibits multiple mTORC1-dependent processes and has robust immunosuppressive effects | 219,220 |
| Hydrogen sulfide | AMPK activation? | Yes | Experimental agent | Unclear MOA and potentially toxic for the respiratory trait | 133 |
| Hydroxycitrate | CRM | Unknown | Clinically tested for treatment of diabetes, now discontinued | May cause weight loss upon chronic administration | 163 |
| IFNγ | MAPK activation? | No | In clinical trials, mainly for cancer immunotherapy | Unclear MOA (involves MAPK signalling) | 169 |
| Lithium | Reduction in Ins(1,4,5)P3 and inositol levels | Yes | Approved for treatment of bipolar disorders | Psychoactive agent, inhibits various neuronal functions | 42,50,55 |
| Melatonin* | Altered ROS production | Yes | In clinical trials for the treatment of a wide range of conditions | Potentially interferes with ROS-sensitive processes and has been associated with autophagy inhibition in some models | 97 |
| Metformin | AMPK activation? | Yes | Approved for treatment of type 2 diabetes | Mediates multiple AMPK-unrelated effects, including inhibition of respiratory complex I | 136 |
| Physical exercise | Multiple | NA | NA | Not appropriate for patients affected by cardiovascular or skeletal disorders but safe in most other cases | 7,119,129 |
| Rapamycin (also known as sirolimus) | mTORC1 inhibition | Yes | Approved for use in coronary stents (to prevent transplant rejection) and to treat a rare pulmonary disease | Inhibits multiple mTORC1-dependent processes, has robust immunosuppressive effects and may cause mTORC2 inhibition on chronic administration | 10,22,31,32,38,40, 41,43–47,50,51,56, 60,68–70,77,79,80, 90,95,96,99, 101–103,132,134, 146,180,183,184, 196,198,219,220, 223,225–228,234, 241,244,245, 255,258–260 |
| Resveratrol | CRM | Yes | Nutritional supplement that is available over the counter; in clinical trials for treatment of several disorders | Potentially causes nephrotoxicity at high concentrations | 33,132,147,229,235 |
| Retinoic acid | Unknown | Yes | Approved for cancer therapy (ATRA) | Reported to specifically inhibit CMA in some settings | 100 |
| Simvastatin | AMPK activation? | Yes | Approved for treatment of obesity | Unclear MOA (associated with AMPK activation) and potentially mitochondriotoxic | 99 |
| Spermidine | CRM | Yes | Nutritional supplement that is available over the counter | Degradation products include ROS and potentially cytotoxic aldehydes | 163,230 |
| Temsirolimus (also known as CCI-779) | mTORC1 inhibition | Yes | Approved for cancer therapy | Inhibits multiple mTORC1-dependent processes and has robust immunosuppressive effects | 51 |
| Torins | mTORC1 inhibition | Unknown | Experimental agents | Inhibit multiple mTORC1-dependent processes | 246 |
| Trehalose | Unknown | Yes | In clinical trials for treatment of bipolar disorders, dry eye syndrome and vascular ageing | Unclear MOA (independent of mTORC1) but safe | 39,53,65 |
| Trichostatin A | Unknown | No | Discontinued from clinical tests | Unclear MOA, potentially linked to transcriptional effects | 98 |
| Vorinostat | Unknown | Yes | Approved for cancer therapy | Unclear MOA, potentially linked to transcriptional effects | 115 |
| Inhibitors | |||||
| 3-MA | VPS34 inhibition | Yes | Experimental agent | Inhibits various class III PI3Ks | 10,36,63,76,78–80, 82,84–88,93,96,98, 99,105,243,255 |
| Azithromycin | Unknown | Yes | Approved for treatment of multiple bacterial infections | Unclear MOA, blocks autophagic flux | 187 |
| Bafilomycin A1 | Lysosomal inhibition | Yes | Experimental agent | Inhibitor of lysosomal functions | 36,58,79,86–88,105,180,255 |
| Cardiac glycosides | Na+/K+-ATPase inhibition | Yes | Extensively used in the past for treatment of cardiac disorders | Narrow therapeutic window but specific for autosis | 94 |
| Chloroquine | Lysosomal inhibition | Yes | Extensively used in the past as an antimalarial agent | Inhibitor of lysosomal functions | 100,104,134, 206,215,224 |
| Compound C (also known as dorsomorphin) | AMPK inhibition | Unknown | In preclinical development | Potentially interferes with AMPK-dependent processes | 82 |
| Edavarone | ROS scavenger | Unknown | Experimental agent | Potentially interferes with many ROS-sensitive processes | 89 |
| HCQ | Lysosomal inhibition | Yes | Extensively used in the past as an antimalarial agent | Inhibitor of lysosomal functions | 190,206,215 |
| LY294002 | VPS34 inhibition | Yes | In clinical trials for the treatment of refractory neuroblastoma | Exhibits improved selectivity compared with 3-MA and wortmannin but commonly considered nonspecific | 84 |
| Lys05 | Lysosomal inhibition | Yes | In preclinical development | Exhibits increased potency compared with HCQ | 294 |
| Mdivi-1 | Mitophagy inhibition | Yes | In preclinical development | Inhibitor of mitochondrial fragmentation | 250 |
| Melatonin* | Altered ROS production | Yes | In clinical trials for treatment of a wide panel of conditions | Potentially interferes with ROS-sensitive processes and has been associated with autophagy activation in some models | 73 |
| MRT67307 | ULK1 inhibition | Unknown | In preclinical development | Also inhibits ULK2, IKK and TBK1 | 299 |
| MRT68921 | ULK1 inhibition | Unknown | In preclinical development | Also inhibits ULK2 | 299 |
| NSC185058 | ATG4B inhibition | Unknown | In preclinical development | Exhibits improved selectivity for the autophagic pathway | 297 |
| SAR405 | VPS34 inhibition | Unknown | In preclinical development | Exhibits improved selectivity compared with 3-MA and wortmannin | 295 |
| SBI-0206965 | ULK1 inhibition | Unknown | In preclinical development | Exhibits improved selectivity for the autophagic pathway | 298 |
| VPS34-IN1 | VPS34 inhibition | Unknown | In preclinical development | Exhibits improved selectivity compared with 3-MA and wortmannin | 296 |
| Wortmannin | VPS34 inhibition | No | Experimental agent | Inhibits various class III PI3Ks | 99 |
3-MA, 3-methyladenine; AMPK, AMP-activated protein kinase; ATG4B, autophagy-related 4B cysteine peptidase; ATRA, all-trans-retinoic acid; BECN1, beclin 1; CMA, chaperone-mediated autophagy; CRM, caloric restriction mimetic; HCQ, hydroxychloroquine; IFNγ, interferon-γ; IKK, inhibitor of nuclear factor-κB kinase; Ins(1,4,5)P3, inositol-1,4,5-trisphosphate; MAPK, mitogen-activated protein kinase; MOA, mode of action; mTORC, mechanistic target of rapamycin complex; NA, not applicable; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species; TBK1, TANK-binding kinase 1; ULK, UNC-51-like autophagy activating kinase.
*
Conflicting data exist on the ability of melatonin to modulate autophagy. Adapted with permission from REF. 9, Macmillan Publishers Limited.