Lysosomal membrane stability plays a major role in the cytotoxic activity of the anti-proliferative agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT)
| Autor: | Hiu Chuen Lok, Laila Arzuman, Vera Richardson, Des R. Richardson, Angelica M. Merlot, Zaklina Kovacevic, Sumit Sahni, Elaine Gutierrez, Patric J. Jansson, Darius J.R. Lane, Nicole A. Seebacher, Danuta S. Kalinowski |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Autophagosome Thiosemicarbazones Programmed cell death Antineoplastic Agents Breast Neoplasms Biology Transfection Permeability 03 medical and health sciences Inhibitory Concentration 50 0302 clinical medicine medicine Autophagy Humans HSP70 Heat-Shock Proteins Molecular Biology Cell Proliferation chemistry.chemical_classification Reactive oxygen species Dose-Response Relationship Drug Cell growth Anticholesteremic Agents beta-Cyclodextrins Cell Biology Intracellular Membranes Transport inhibitor Cell biology 030104 developmental biology Cholesterol Mechanism of action chemistry 030220 oncology & carcinogenesis MCF-7 Cells Androstenes Female RNA Interference medicine.symptom Lysosomes |
| Zdroj: | Biochimica et biophysica acta. 1863(7 Pt) |
| ISSN: | 0006-3002 |
| Popis: | The potent and selective anti-tumor agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), localizes in lysosomes and forms cytotoxic copper complexes that generate reactive oxygen species (ROS), resulting in lysosomal membrane permeabilization (LMP) and cell death. Herein, the role of lysosomal membrane stability in the anti-tumor activity of Dp44mT was investigated. Studies were performed using molecules that protect lysosomal membranes against Dp44mT-induced LMP, namely heat shock protein 70 (HSP70) and cholesterol. Up-regulation or silencing of HSP70 expression did not affect Dp44mT-induced LMP in MCF7 cells. In contrast, cholesterol accumulation in lysosomes induced by the well characterized cholesterol transport inhibitor, 3-β-[2-(diethyl-amino)ethoxy]androst-5-en-17-one (U18666A), inhibited Dp44mT-induced LMP and markedly and significantly (p |
| Databáze: | OpenAIRE |
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