期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 50, 期 1, 页码 110-121出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2010.10.696
关键词
Thiosemicarbazone; Copper; ER stress; UPR; Macroautophagy; Oxidative stress; Free radicals
资金
- National Cancer Institute, National Institutes of Health [HHSN261200800001E]
- Division of Cancer Treatment and Diagnosis of the National Cancer Institute
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/Cu2+ 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/Cu2+-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/Cu2+-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. (C) 2010 Elsevier Inc. All rights reserved.
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