@article{958f18d4ac164948b989f8bd0301f28a,
title = "A copper chelate of thiosemicarbazone NSC 689534 induces oxidative/ER stress and inhibits tumor growth in vitro and in vivo",
abstract = "In this study, a Cu2+ chelate of the novel thiosemicarbazone NSC 689534 was evaluated for in vitro and in vivo anti-cancer activity. Results demonstrated that NSC 689534 activity (low micromolar range) was enhanced four- to fivefold by copper chelation and completely attenuated by iron. Importantly, once formed, the NSC 689534/Cu2+ complex retained activity in the presence of additional iron or iron-containing biomolecules. NSC 689534/Cu 2+ mediated its effects primarily through the induction of ROS, with depletion of cellular glutathione and protein thiols. Pretreatment of cells with the antioxidant N-acetyl-l-cysteine impaired activity, whereas NSC 689534/Cu2+ effectively synergized with the glutathione biosynthesis inhibitor buthionine sulfoximine. Microarray analysis of NSC 689534/Cu 2+-treated cells highlighted activation of pathways involved in oxidative and ER stress/UPR, autophagy, and metal metabolism. Further scrutiny of the role of ER stress and autophagy indicated that NSC 689534/Cu 2+-induced cell death was ER-stress dependent and autophagy independent. Last, NSC 689534/Cu2+ was shown to have activity in an HL60 xenograft model. These data suggest that NSC 689534/Cu2+ is a potent oxidative stress inducer worthy of further preclinical investigation.",
keywords = "Copper, ER stress, Free radicals, Macroautophagy, Oxidative stress, Thiosemicarbazone, UPR",
author = "Hancock, {Chad N.} and Stockwin, {Luke H.} and Bingnan Han and Divelbiss, {Raymond D.} and Jun, {Jung Ho} and Malhotra, {Sanjay V.} and Hollingshead, {Melinda G.} and Newton, {Dianne L.}",
note = "Funding Information: We gratefully acknowledge the excellent technical assistance of Ms. Sherry Yu. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. This research was supported (in part) by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NCI–Frederick is accredited by AAALACi and follows the Public Health Service Policy on the Care and Use of Laboratory Animals. All animals used in this research project were cared for and used humanely according to the following policies: the U.S. Public Health Service Policy on Humane Care and Use of Animals (1996), the Guide for the Care and Use of Laboratory Animals (1996), and the U.S. government Principles for Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training (1985). Copyright: Copyright 2011 Elsevier B.V., All rights reserved.",
year = "2011",
month = jan,
day = "1",
doi = "10.1016/j.freeradbiomed.2010.10.696",
language = "English (US)",
volume = "50",
pages = "110--121",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",
number = "1",
}