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 language | English (US) |
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Pages (from-to) | 110-121 |
Number of pages | 12 |
Journal | Free Radical Biology and Medicine |
Volume | 50 |
Issue number | 1 |
DOIs | |
State | Published - Jan 1 2011 |
Externally published | Yes |
Keywords
- Copper
- ER stress
- Free radicals
- Macroautophagy
- Oxidative stress
- Thiosemicarbazone
- UPR
ASJC Scopus subject areas
- Biochemistry
- Physiology (medical)