Autophagy modulation: a target for cancer treatment development
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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.
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.
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.
The preclinical evidence for modulating autophagy describes a promising, novel mechanism for enhancing anticancer treatments and overcoming current challenges such as chemotherapy resistance.
KeywordsAutophagy Hydroxychloroquine Cell death
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.
- 19.Funakoshi T, Latif A, Galsky MD (2014) Safety and efficacy of addition of VEGFR and EGFR-family oral small-molecule tyrosine kinase inhibitors to cytotoxic chemotherapy in solid cancers: a systematic review and meta-analysis of randomized controlled trials. Cancer Treat Rev. doi: 10.1016/j.ctrv.2014.02.004 Google Scholar
- 24.Mahalingam D, Mita M, Sarantopoulos J et al (2014) Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy 10:1403–1414. doi: 10.4161/auto.29231 CrossRefPubMedGoogle Scholar
- 27.Barnard RA, Wittenburg LA, Amaravadi RK et al (2014) Phase I clinical trial and pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma. Autophagy 10:1415–1425. doi: 10.4161/auto.29165 CrossRefPubMedGoogle Scholar
- 29.Zhou C, Wu Y-L, Chen G et al (2011) Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 12:735–742. doi: 10.1016/S1470-2045(11)70184-X CrossRefPubMedGoogle Scholar