A copper chelate of thiosemicarbazone NSC 689534 induces oxidative/ER stress and inhibits tumor growth in vitro and in vivo

Chad N. Hancock, Luke H. Stockwin, Bingnan Han, Raymond D. Divelbiss, Jung Ho Jun, Sanjay V. Malhotra, Melinda G. Hollingshead, Dianne L. Newton

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)110-121
Number of pages12
JournalFree Radical Biology and Medicine
Volume50
Issue number1
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

Keywords

  • Copper
  • ER stress
  • Free radicals
  • Macroautophagy
  • Oxidative stress
  • Thiosemicarbazone
  • UPR

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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