A copper chelate of thiosemicarbazone NSC 689534 induces oxidative/ER stress and inhibits tumor growth in vitro and in vivo. Hancock, C. N., Stockwin, L. H., Han, B., Divelbiss, R. D., Jun, J. H., Malhotra, S. V., Hollingshead, M. G., & Newton, D. L. Free Radical Biology & Medicine, 50(1):110–121, January, 2011.
doi  abstract   bibtex   
In this study, a Cu(2+) 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/Cu(2+) 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/Cu(2+) 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/Cu(2+) was shown to have activity in an HL60 xenograft model. These data suggest that NSC 689534/Cu(2+) is a potent oxidative stress inducer worthy of further preclinical investigation.
@article{hancock_copper_2011,
	title = {A copper chelate of thiosemicarbazone {NSC} 689534 induces oxidative/{ER} stress and inhibits tumor growth in vitro and in vivo},
	volume = {50},
	issn = {1873-4596},
	doi = {10.1016/j.freeradbiomed.2010.10.696},
	abstract = {In this study, a Cu(2+) 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/Cu(2+) 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/Cu(2+) 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/Cu(2+) was shown to have activity in an HL60 xenograft model. These data suggest that NSC 689534/Cu(2+) is a potent oxidative stress inducer worthy of further preclinical investigation.},
	language = {eng},
	number = {1},
	journal = {Free Radical Biology \& Medicine},
	author = {Hancock, Chad N. and Stockwin, Luke H. and Han, Bingnan and Divelbiss, Raymond D. and Jun, Jung Ho and Malhotra, Sanjay V. and Hollingshead, Melinda G. and Newton, Dianne L.},
	month = jan,
	year = {2011},
	pmid = {20971185},
	pmcid = {PMC3014388},
	keywords = {Animals, Antineoplastic Agents, Cell Proliferation, Chelating Agents, Copper, Down-Regulation, Endoplasmic Reticulum, Female, HL-60 Cells, Humans, Mice, Mice, Nude, Neoplasms, Organometallic Compounds, Oxidants, Oxidative Stress, Thiosemicarbazones, Tumor Cells, Cultured, Unfolded Protein Response, Up-Regulation, Xenograft Model Antitumor Assays},
	pages = {110--121},
}
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