Biphasic Activity of Chloroquine in Human Colorectal Cancer Cells
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초록
Autophagy is a homeostatic degradation process that is involved in tumor development and normaldevelopment. Autophagy is induced in cancer cells in response to chemotherapeutic agents, and inhibition of autophagyresults in enhanced cancer cell death or survival. Chloroquine (CQ), an anti-malarial drug, is a lysosomotropic agent and iscurrently used as a potential anticancer agent as well as an autophagy inhibitor. Here, we evaluate the characteristics of thesedual activities of CQ using human colorectal cancer cell line HCT15. The results show that CQ inhibited cell viability in doseandtime-dependent manner in the range between 20 to 80 uM, while CQ did not show any antiproliferative activity at 5 and10 uM. Cotreatment of CQ with antitumor agent NVP-BEZ235, a dual inhibitor of PI3K/mTOR, rescued the cell viability atlow concentrations meaning that CQ acted as an autophagy inhibitor, but CQ induced the lethal effect at high concentrations. Acridine orange staining revealed that CQ at high doses induced lysosomal membrane permeabilization (LMP). High doses ofCQ produced cellular reactive oxygen species (ROS) and cotreatment of antioxidants, such as NAC and trolox, with highdoses of CQ rescued the cell viability. These results suggest that CQ may exert its dual activities, as autophagy inhibitor orLMP inducer, in concentration-dependent manner.
Abstract
Autophagy is a homeostatic degradation process that is involved in tumor development and normaldevelopment. Autophagy is induced in cancer cells in response to chemotherapeutic agents, and inhibition of autophagyresults in enhanced cancer cell death or survival. Chloroquine (CQ), an anti-malarial drug, is a lysosomotropic agent and iscurrently used as a potential anticancer agent as well as an autophagy inhibitor. Here, we evaluate the characteristics of thesedual activities of CQ using human colorectal cancer cell line HCT15. The results show that CQ inhibited cell viability in doseandtime-dependent manner in the range between 20 to 80 uM, while CQ did not show any antiproliferative activity at 5 and10 uM. Cotreatment of CQ with antitumor agent NVP-BEZ235, a dual inhibitor of PI3K/mTOR, rescued the cell viability atlow concentrations meaning that CQ acted as an autophagy inhibitor, but CQ induced the lethal effect at high concentrations. Acridine orange staining revealed that CQ at high doses induced lysosomal membrane permeabilization (LMP). High doses ofCQ produced cellular reactive oxygen species (ROS) and cotreatment of antioxidants, such as NAC and trolox, with highdoses of CQ rescued the cell viability. These results suggest that CQ may exert its dual activities, as autophagy inhibitor orLMP inducer, in concentration-dependent manner.
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