title: Simultaneous activation and inhibition of autophagy sensitizes cancer cells to chemotherapy.
abstract: While combined chemotherapy (CT) with an autophagy inducer and an autophagy inhibitor appears paradoxical, it may provide a more effective perturbation of autophagy pathways. We used two dissimilar cell lines to test the hypothesis that autophagy is the common denominator of cell fate after CT. HA22T cells are characterized by CT-induced apoptosis and use autophagy to prevent cell death, while Huh7.5.1 cells exhibit sustained autophagic morphology after CT. Combined CT and rapamycin treatment resulted in a better combination index (CI) in Huh7.5.1 cells than combined CT and chloroquine, while the reverse was true in HA22T cells. The combination of 3 drugs (triplet drug treatment) had the best CI. After triplet drug treatment, HA22T cells switched from protective autophagy to mitochondrial membrane permeabilization and endoplasmic reticulum stress response-induced apoptosis, while Huh7.5.1 cells intensified autophagic lethality. Most importantly, both cell lines showed activation of Akt after CT, while the triplet combination blocked Akt activation through inhibition of phospholipid lipase D activity. This novel finding warrants further investigation as a broad chemosensitization strategy.
authors.affiliation: Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.|Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.|Institute of Veterinary Clinical Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Kwan-Hwa
authors.initials: KH
authors.lastname: Chi
authors.affiliation: Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.|Department of Research and Development, JohnPro Biotech Inc., Taipei, Taiwan.
authors.forename: Yu-Shan
authors.initials: YS
authors.lastname: Wang
authors.affiliation: Department of Research and Development, JohnPro Biotech Inc., Taipei, Taiwan.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Huang
authors.affiliation: Department of Research and Development, JohnPro Biotech Inc., Taipei, Taiwan.
authors.forename: Hsin-Chien
authors.initials: HC
authors.lastname: Chiang
authors.affiliation: Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Mau-Shin
authors.initials: MS
authors.lastname: Chi
authors.affiliation: Institute of Veterinary Clinical Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Chau-Hwa
authors.initials: CH
authors.lastname: Chi
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hsin-Ell
authors.initials: HE
authors.lastname: Wang
authors.affiliation: Division of Pulmonary Medicine, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Shang-Jyh
authors.initials: SJ
authors.lastname: Kao
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051336:Mitochondrial Membranes / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D010739:Phospholipase D / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014748:Vinca Alkaloids / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D017382:Reactive Oxygen Species; D014748:Vinca Alkaloids; D002738:Chloroquine; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D010739:Phospholipase D; D020123:Sirolimus
keywords: autophagy; chemosensitization; chloroquine; rapamycin; synthetic lethality