Simultaneous activation and inhibition of autophagy sensitizes cancer cells to chemotherapy

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. HA22...

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Bibliographic Details
Published in:Oncotarget 2016-09, Vol.7 (36), p.58075-58088
Main Authors: Chi, Kwan-Hwa, Wang, Yu-Shan, Huang, Yi-Chun, Chiang, Hsin-Chien, Chi, Mau-Shin, Chi, Chau-Hwa, Wang, Hsin-Ell, Kao, Shang-Jyh
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Apoptosis - drug effects
Autophagy - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Chloroquine - pharmacology
Chloroquine - therapeutic use
Drug Resistance, Neoplasm
Drug Synergism
Endoplasmic Reticulum Stress - drug effects
Humans
Male
Mice
Mice, Inbred NOD
Mice, SCID
Mitochondrial Membranes - metabolism
Neoplasms - drug therapy
Phospholipase D - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Reactive Oxygen Species - metabolism
Research Paper
Signal Transduction - drug effects
Sirolimus - pharmacology
Sirolimus - therapeutic use
TOR Serine-Threonine Kinases - metabolism
Vinca Alkaloids - pharmacology
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.10873