Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

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Key Points

  • Autophagy is a catabolic process through which eukaryotic cells degrade disposable, ectopic or damaged cytoplasmic material.

  • The inhibition or hyperactivation of autophagy has been linked to the pathogenesis of a wide range of clinically relevant conditions that affect all organs, including neurodegeneration, cardiac disorders and cancer.

  • Pharmacological or nutritional interventions that activate or inhibit autophagy are expected to mediate beneficial effects in multiple clinical settings.

  • The development of clinically viable modulators of autophagy has been hampered by specificity issues, technical problems and murine models that suffer from multiple limitations.

  • Overcoming these obstacles is key to obtaining further insights into autophagy and its intricate relationship with other cellular processes, and hence to unlocking the full therapeutic potential of autophagy modulators.

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.

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Figure 1: Autophagic processes amenable to therapeutic modulation.
Figure 2: Principles of autophagy modulation.

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Acknowledgements

Owing to space limitations, the authors apologize to the authors of several high-quality articles in the field for not being able to discuss and cite their work. L.G. is supported by the Department of Radiation Oncology of Weill Cornell Medical College (intramural funds) and Sotio a.c. J.M.B.-S.P. and G.K. are supported by the French Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR), Projets blancs; ANR under the frame of the programme E-Rare-2, the European Research Area (ERA)-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Institut Universitaire de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LeDucq Foundation; the LabEx Immuno-Oncology; the Site de Recherche Intégrée sur le Cancer (SIRIC) Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). B.L. is supported by the National Institutes of Health, Cancer Prevention Research Institute of Texas, and the LeDucq Foundation. D.R.G. is supported by the National Institutes of Health and the American Lebanese Syrian Associated Charities (ALSAC).

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Correspondence to Lorenzo Galluzzi.

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The authors declare no competing financial interests.

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ClinicalTrials.gov

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Glossary

Autophagic cell death

A variant of regulated cell death (RCD) that is precipitated by the autophagic machinery and hence can be retarded with pharmacological or genetic inhibitors of autophagy.

Regulated cell death

(RCD). A form of cell death that relies on the activation of genetically encoded machinery and hence can be retarded or accelerated with specific pharmacological or genetic interventions.

Mitophagy

Autophagic response that is specific for depolarized or otherwise damaged mitochondria.

Aggrephagy

Autophagic response that is specific for intracellular protein aggregates, which often are highly ubiquitylated.

Presenilin 1

(PSEN1). Component of the γ-secretase complex that contributes to the accumulation of amyloid plaques in the brain of patients with Alzheimer disease (AD).

Autophagic adaptor

A protein that directs autophagic substrates to forming autophagosomes through its capacity to bind ubiquitylated structures and lipidated Atg8 family members.

Amyloid-β precursor protein

(APP). A protein that — upon cleavage — accounts for the majority of amyloid plaques in the brain of patients with Alzheimer disease (AD).

Caloric restriction mimetic

(CRM). A molecule that mimics the biochemical and cellular effects of fasting, including autophagy activation and cytosolic acetyl-CoA depletion, but does not provoke a sizeable weight loss.

Trehalose

A natural α-linked disaccharide that potently activates autophagy through poorly characterized mechanisms.

Valproate

A widely used antiepileptic drug that induces autophagy by affecting myo-inositol-1,4,5-trisphosphate levels.

Lithium

An antidepressant that promotes autophagic responses by altering myo-inositol-1,4,5-trisphosphate levels.

Locomotor sensitization

Long-lasting exacerbation of a psychostimulant-induced locomotor response, which is brought about by repeated intermittent administration of the same psychoactive agent.

Ischaemic preconditioning

An experimental technique for increasing the resistance of neurons or cardiomyocytes to prolonged, severe ischaemia based on the repeated administration of short, mild ischaemic episodes.

Cardiac glycoside

A natural compound that exerts positive inotropic effects and retards some forms of autophagic cell death as it inhibits the plasma membrane Na+/K+-ATPase.

Efferocytosis

The removal of dying or dead cells by professional phagocytes.

Spermidine

A natural polyamine that potently activates autophagy by operating as a caloric restriction mimetic (CRM).

Coronary angioplasty

A minimally invasive surgical procedure for the treatment of narrowed or weakened arteries, which consists of the insertion of a small mesh tube (stent) through the femoral artery.

Metformin

An antidiabetic agent with pleiotropic effects, including the capacity to trigger autophagy by acting as a caloric restriction mimetic (CRM).

db/db mice

Mice homozygous for the spontaneous db (for diabetes) mutation in leptin receptor (Lepr), which causes limited leptin signalling. These animals are commonly used as models for type 2 diabetes and metabolic syndrome.

ob/ob mice

Mice homozygous for the spontaneous ob (for obesity) mutation in leptin receptor (Lepr), which causes absent leptin signalling. These animals are commonly used as models for obesity and metabolic syndrome.

Carbamazepine

A widely used antiepileptic drug that induces autophagy by altering myo-inositol-1,4,5-triphosphate levels.

α1-antitrypsin deficiency

A genetic disease that causes the defective production of serpin family A member 1 (SERPINA1; also known as α1-antitrypsin) in the lungs and liver, which results in pulmonary disorders that are often associated with hepatic symptoms.

Streptozotocin

A naturally occurring toxin that is commonly used to generate rodent models of type 1 diabetes owing to its pronounced selectivity for pancreatic β-cells.

Malignant transformation

The conversion of a healthy, normal cell into a neoplastic cell precursor. Malignant transformation is insufficient to drive tumorigenesis.

Oncosuppressor genes

Genes mutated or silenced in familial or sporadic forms of cancer. Many of these genes encode proteins that are involved in the maintenance of cellular homeostasis or in the activation of regulated cell death (RCD).

Proto-oncogenes

Genes overexpressed or hyperactivated in familial or sporadic forms of cancer. Many of these genes encode positive regulators of cellular proliferation or proteins that inhibit regulated cell death (RCD).

Tumour progression

A process through which a neoplastic cell precursor acquires additional genetic or epigenetic alterations that allow it to escape cell-intrinsic and cell-extrinsic control mechanisms and form aggressive tumours.

Immunosurveillance

A process in which the immune system recognizes and eliminates a potentially dangerous entity, including invading pathogens as well as pre-malignant and malignant cells.

Inflammasomes

Supramolecular platforms that support caspase 1 activation, hence allowing for the proteolytic maturation and secretion of pro-inflammatory interleukin-1β (IL-1β) and IL-18.

Neutrophil extracellular traps

(NETs). Chromatin-based and granule protein-containing fibres that are released by neutrophils to immobilize and kill invading microorganisms.

Cellular senescence

A permanent proliferative arrest that is generally associated with specific morphological and biochemical features, including the secretion of multiple cytokines and other biologically active factors.

Chronic obstructive pulmonary disease

(COPD). A progressive lung disease that is characterized by long-term limited airflow, which is often caused or aggravated by tobacco smoke.

Focal segmental glomerulosclerosis

A leading cause of kidney failure in adults that is characterized by the degeneration of sections of the glomerulus with a focal (as opposed to diffuse) intrarenal distribution.

Glucosylceramide

A sphingolipid that accumulates in patients with Gaucher disease (mostly in the macrophages) as a result of mutations in glucosylceramidase beta (GBA).

Retinitis pigmentosa

An inherited, degenerative eye disease that causes severe vision impairment owing to the progressive degeneration of the rod photoreceptor cells.

Rapalogues

Rapamycin derivatives with improved pharmacodynamic and pharmacokinetic properties.

Canonical autophagy

A term commonly used to refer to an autophagic response that is dependent on autophagy-related 5 (ATG5), ATG7, beclin 1 (BECN1) and phosphatidylinositol-3-phosphate (PtdIns3P) production.

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Galluzzi, L., Bravo-San Pedro, J., Levine, B. et al. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov 16, 487–511 (2017) doi:10.1038/nrd.2017.22

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