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Antitumor Activity of Metal-Chelating Compound Dp44mT Is Mediated by Formation of a Redox-Active Copper Complex That Accumulates in Lysosomes
University of Sydney.
University of Sydney.
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
University of Sydney.
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2011 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 71, no 17, 5871-5880 p.Article in journal (Refereed) Published
Abstract [en]

The metal-chelating compound Dp44mT is a di-2-pyridylketone thiosemicarbazone (DpT) which displays potent and selective antitumor activity. This compound is receiving translational attention, but its mechanism is poorly understood. Here, we report that Dp44mT targets lysosome integrity through copper binding. Studies using the lysosomotropic fluorochrome acridine orange established that the copper-Dp44mT complex (Cu[Dp44mT]) disrupted lysosomes. This targeting was confirmed with pepstatin A-BODIPY FL, which showed redistribution of cathepsin D to the cytosol with ensuing cleavage of the proapoptotic BH3 protein Bid. Redox activity of Cu[Dp44mT] caused cellular depletion of glutathione, and lysosomal damage was prevented by cotreatment with the glutathione precursor N-acetylcysteine. Copper binding was essential for the potent antitumor activity of Dp44mT, as coincubation with nontoxic copper chelators markedly attenuated its cytotoxicity. Taken together, our studies show how the lysosomal apoptotic pathway can be selectively activated in cancer cells by sequestration of redox-active copper. Our findings define a novel generalized strategy to selectively target lysosome function for chemotherapeutic intervention against cancer.

Place, publisher, year, edition, pages
American Association for Cancer Research , 2011. Vol. 71, no 17, 5871-5880 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-70738DOI: 10.1158/0008-5472.CAN-11-1218ISI: 000294454700028OAI: oai:DiVA.org:liu-70738DiVA: diva2:441423
Note
Funding Agencies|National Health and Medical Research Council||Cancer Institute NSW||Available from: 2011-09-16 Created: 2011-09-16 Last updated: 2017-12-08

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Brunk, Ulf

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