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.