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.
Highlights
Resistance to chemotherapeutics has become a major obstacle in successful cancer treatment, and there is an urgent need to develop novel treatment strategies [1]
combination index (CI) suggested a synergistic effect at the level of 30–70% inhibition for treatment with CQ and Rapa, plus vinorelbine or docetaxel, in HA22T cells; a similar effect was observed for Huh7.5.1 cells (Table 1)
We have demonstrated that simultaneous activation and inhibition of autophagy by CQ and Rapa combination treatment is a novel therapeutic strategy for CT sensitization
Summary
Resistance to chemotherapeutics has become a major obstacle in successful cancer treatment, and there is an urgent need to develop novel treatment strategies [1]. Apoptosis events are usually preceded by autophagy-dependent survival signals, while inhibition of autophagy usually promotes apoptotic cell death [10]. Chloroquine (CQ), a commonly used autophagy inhibitor, has been shown to reverse CT resistance in cultured cells, animal models, and patients [11]. It is still controversial whether CQ enhances the cytotoxic effects of everolimus [12, 13]. It is not clear whether autophagy promotes or inhibits drug sensitivity. Current data suggest that mTOR inhibition by everolimus should increase the efficacy of CT or hormone therapy in breast cancers [14, 15]
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