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Cancer Chemotherapy and Pharmacology

, Volume 75, Issue 3, pp 439–447 | Cite as

Autophagy modulation: a target for cancer treatment development

  • Alison Duffy
  • Jackson Le
  • Edward Sausville
  • Ashkan Emadi
Review Article

Abstract

Purpose

Regulation of cellular death is a complex method to maintain cellular homeostasis by protecting against oncogenic development and by recycling damaged cellular debris. Dysregulation of autophagy cellular death is common among a wide range of cancers and presents challenges to current treatment options. This review will evaluate current methods to directly and indirectly modulate autophagy to prevent cancer and to overcome resistance to anticancer therapy.

Methods

PubMed was searched for keywords: autophagy, hydroxychloroquine, chloroquine, and cell death for preclinical and clinical studies evaluating autophagy-modulating pathways and compounds. Clinicaltrials.gov was searched for keywords: autophagy, hydroxychloroquine, and chloroquine for clinical trials involving autophagy.

Results

The pathways of autophagy are highly prevalent in numerous cancers cell types including leukemia, renal cell cancer, non-small cell lung cancer, melanoma, and advanced solid tumor. Autophagy-inducing compounds represent various drug classes and include everolimus, bortezomib, vorinostat, and arsenic trioxide. The autophagy-inhibiting compounds include chloroquine, hydroxychloroquine, and bafilomycin. Clinicaltrials.gov search identified 32 currently ongoing clinical studies evaluating autophagy and included 14 and 3 studies involving hydroxychloroquine and chloroquine, respectively. These phase I and phase II studies, evaluating the therapeutic benefit of combining autophagy modulators with current anticancer treatments, demonstrate early evidence for application in resistant cancer therapy. Despite positive results, there remains a need to identify direct-acting autophagy inhibitors and for larger phase III trials to be conducted.

Conclusion

The preclinical evidence for modulating autophagy describes a promising, novel mechanism for enhancing anticancer treatments and overcoming current challenges such as chemotherapy resistance.

Keywords

Autophagy Hydroxychloroquine Cell death 

Notes

Acknowledgments

This review is supported by Dr. Emadi’s Research Foundation Account at University of Maryland Greenebaum Cancer Center (UMGCC) for figure illustration funding. Illustration artwork was performed by John Ott.

Conflict of interest

The authors report no relevant conflicts of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Alison Duffy
    • 1
  • Jackson Le
    • 2
  • Edward Sausville
    • 3
  • Ashkan Emadi
    • 3
  1. 1.Marlene and Stewart Greenebaum Cancer CenterUniversity of Maryland School of PharmacyBaltimoreUSA
  2. 2.Geisinger Health PlanDanvilleUSA
  3. 3.Marlene and Stewart Greenebaum Cancer CenterUniversity of Maryland School of MedicineBaltimoreUSA

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