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Biphasic Activity of Chloroquine in Human Colorectal Cancer Cells

Autophagy is a homeostatic degradation process that is involved in tumor development and normal development. Autophagy is induced in cancer cells in response to chemotherapeutic agents, and inhibition of autophagy results in enhanced cancer cell death or survival. Chloroquine (CQ), an anti-malarial...

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Autores principales: Park, Deokbae, Lee, Youngki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Korean Society of Developmental Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415643/
https://www.ncbi.nlm.nih.gov/pubmed/25949192
http://dx.doi.org/10.12717/DR.2014.18.4.225
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author Park, Deokbae
Lee, Youngki
author_facet Park, Deokbae
Lee, Youngki
author_sort Park, Deokbae
collection PubMed
description Autophagy is a homeostatic degradation process that is involved in tumor development and normal development. Autophagy is induced in cancer cells in response to chemotherapeutic agents, and inhibition of autophagy results in enhanced cancer cell death or survival. Chloroquine (CQ), an anti-malarial drug, is a lysosomotropic agent and is currently used as a potential anticancer agent as well as an autophagy inhibitor. Here, we evaluate the characteristics of these dual activities of CQ using human colorectal cancer cell line HCT15. The results show that CQ inhibited cell viability in dose-and time-dependent manner in the range between 20 to 80 uM, while CQ did not show any antiproliferative activity at 5 and 10 uM. Cotreatment of CQ with antitumor agent NVP-BEZ235, a dual inhibitor of PI3K/mTOR, rescued the cell viability at low 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 of CQ produced cellular reactive oxygen species (ROS) and cotreatment of antioxidants, such as NAC and trolox, with high doses of CQ rescued the cell viability. These results suggest that CQ may exert its dual activities, as autophagy inhibitor or LMP inducer, in concentration-dependent manner.
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spelling pubmed-44156432015-05-06 Biphasic Activity of Chloroquine in Human Colorectal Cancer Cells Park, Deokbae Lee, Youngki Dev Reprod Article Autophagy is a homeostatic degradation process that is involved in tumor development and normal development. Autophagy is induced in cancer cells in response to chemotherapeutic agents, and inhibition of autophagy results in enhanced cancer cell death or survival. Chloroquine (CQ), an anti-malarial drug, is a lysosomotropic agent and is currently used as a potential anticancer agent as well as an autophagy inhibitor. Here, we evaluate the characteristics of these dual activities of CQ using human colorectal cancer cell line HCT15. The results show that CQ inhibited cell viability in dose-and time-dependent manner in the range between 20 to 80 uM, while CQ did not show any antiproliferative activity at 5 and 10 uM. Cotreatment of CQ with antitumor agent NVP-BEZ235, a dual inhibitor of PI3K/mTOR, rescued the cell viability at low 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 of CQ produced cellular reactive oxygen species (ROS) and cotreatment of antioxidants, such as NAC and trolox, with high doses of CQ rescued the cell viability. These results suggest that CQ may exert its dual activities, as autophagy inhibitor or LMP inducer, in concentration-dependent manner. Korean Society of Developmental Biology 2014-12 /pmc/articles/PMC4415643/ /pubmed/25949192 http://dx.doi.org/10.12717/DR.2014.18.4.225 Text en © Copyright an Official Journal of the Korean Society of Developmental Biology. All Rights Reserve http://creativecommons.org/licenses/by-nc/3.0/ This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Article
Park, Deokbae
Lee, Youngki
Biphasic Activity of Chloroquine in Human Colorectal Cancer Cells
title Biphasic Activity of Chloroquine in Human Colorectal Cancer Cells
title_full Biphasic Activity of Chloroquine in Human Colorectal Cancer Cells
title_fullStr Biphasic Activity of Chloroquine in Human Colorectal Cancer Cells
title_full_unstemmed Biphasic Activity of Chloroquine in Human Colorectal Cancer Cells
title_short Biphasic Activity of Chloroquine in Human Colorectal Cancer Cells
title_sort biphasic activity of chloroquine in human colorectal cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415643/
https://www.ncbi.nlm.nih.gov/pubmed/25949192
http://dx.doi.org/10.12717/DR.2014.18.4.225
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