title: You eat what you are: autophagy inhibition as a therapeutic strategy in leukemia.
abstract: A deeper understanding of the role of autophagy, literally 'self-eating', in normal and cancer cell biology has emerged over the last few years. Autophagy serves as a vehicle for cells to respond to various stressors including genomic, hypoxic and nutrient stress, and to oppose mechanisms of 'programmed' cell death. Here, we review not only mechanisms of cell death and cell survival but also the early successes in applying autophagy inhibition strategies in solid tumors using the only currently available clinical inhibitor, oral hydroxychloroquine. In acute leukemia, currently available chemotherapy drugs promote cell death and demonstrate clinical benefit, but relapse and subsequent chemotherapy resistance is common. Increasing preclinical data suggest that autophagy is active in leukemia as a means of promoting cell survival in response to chemotherapy. We propose coupling autophagy inhibition strategies with current cytotoxic chemotherapy and discuss synergistic combinations of available anti-leukemic therapies with autophagy inhibition. Furthermore, novel autophagy inhibitors are in development and promise to provide new therapeutic opportunities for patients with leukemia.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Sehgal
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Konig
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Johnson
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Tang
authors.affiliation: Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Amaravadi
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Boyiadzis
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Lotze
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D002470:Cell Survival / Q000187:drug effects; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015870:Gene Expression; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006886:Hydroxychloroquine / Q000627:therapeutic use; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D011719:Pyrazines / Q000627:therapeutic use; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D011719:Pyrazines; D006886:Hydroxychloroquine; C401859:temsirolimus; D000069286:Bortezomib; D020123:Sirolimus