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Review
. 2017 Jul;16(7):487-511.
doi: 10.1038/nrd.2017.22. Epub 2017 May 19.

Pharmacological Modulation of Autophagy: Therapeutic Potential and Persisting Obstacles

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Free PMC article
Review

Pharmacological Modulation of Autophagy: Therapeutic Potential and Persisting Obstacles

Lorenzo Galluzzi et al. Nat Rev Drug Discov. .
Free PMC article

Abstract

Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Accordingly, alterations in autophagy have been linked to clinically relevant conditions as diverse as cancer, neurodegeneration and cardiac disorders. Throughout the past decade, autophagy has attracted considerable attention as a target for the development of novel therapeutics. However, such efforts have not yet generated clinically viable interventions. In this Review, we discuss the therapeutic potential of autophagy modulators, analyse the obstacles that have limited their development and propose strategies that may unlock the full therapeutic potential of autophagy modulation in the clinic.

Conflict of interest statement

Competing interests statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1. Autophagic processes amenable to therapeutic modulation
Several pharmacological and nutritional interventions are available to inhibit autophagy at the nucleation, elongation, fusion or degradation phase. In addition, several agents modulate autophagy through multipronged or hitherto uncharacterized molecular mechanisms. For additional details, please refer to TABLE 1. 3-MA, 3-methyladenine; AMPK, AMP-activated protein kinase; ATG4B, autophagy-related 4B cysteine peptidase; BafA1, bafilomycin A1; BECN1, beclin 1; CRM, caloric restriction mimetic; H2S, hydrogen sulfide; HCQ, hydroxychloroquine; IFNγ, interferon-γ; Ins(1,4,5)P3, inositol-1,4,5-trisphosphate; MAPK, mitogen-activated protein kinase; mTORC1, mechanistic target of rapamycin complex 1; ROS, reactive oxygen species; ULK1, UNC-51-like autophagy activating kinase 1.
Figure 2
Figure 2. Principles of autophagy modulation
a | When autophagy mechanistically contributes to the aetiology of the disease, inhibiting autophagy initiation in diseased cells is expected to restore normal autophagic degradation and mediate therapeutic effects, whereas blocking lysosomal degradation may favour a detrimental accumulation of non-functional autophagosomes and autolysosomes. b | In the presence of initiation defects, stimulating autophagy upstream of autophagosome formation (in diseased cells) is expected to normalize autophagic flux (at least in part) and hence mediate beneficial effects, whereas boosting lysosomal degradation may exert limited (if any) therapeutic activity. c | In the presence of degradation defects, activating autophagy upstream of autophagosome formation (in diseased cells) may aggravate disease severity by exacerbating (thick arrows) the accumulation of non-functional autophagosomes and autolysosomes. Conversely, accelerating lysosomal degradation or inhibiting initiation (in diseased cells) may exert beneficial effects, at least to some degree (dashed arrow). d | Boosting autophagic flux in cells that survived a pathological insult or in non‐diseased cells may favour functional recovery and/or mediate beneficial effects linked to improved inflammatory tissue homeostasis. Beneficial and detrimental interventions are indicated by green and red arrows, respectively.
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