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

  1. Author:
    Hancock, C. N.
    Stockwin, L. H.
    Han, B. N.
    Divelbiss, R. D.
    Jun, J. H.
    Malhotra, S. V.
    Hollingshead, M. G.
    Newton, D. L.

  2. Author Address

    [Hancock, Chad N.; Stockwin, Luke H.; Han, Bingnan; Divelbiss, Raymond D.; Newton, Dianne L.] SAIC Frederick, Biol Testing Branch, Dev Therapeut Program, Frederick, MD 21702 USA. [Jun, Jung Ho; Malhotra, Sanjay V.] SAIC Frederick Inc, Lab Synthet Chem, Frederick, MD 21702 USA. [Hollingshead, Melinda G.] NCI, Biol Testing Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA.;Newton, DL, SAIC Frederick, Biol Testing Branch, Dev Therapeut Program, Frederick, MD 21702 USA.;newtondianne@mail.nih.gov
    1. Year: 2011
    2. Date: Jan
  2. Journal: Free Radical Biology and Medicine
    1. 50
    2. 1
    3. Pages: 110-121
  4. Type of Article: Article
  5. ISSN: 0891-5849
  1. 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/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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External Sources

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  2. DOI: 10.1016/j.freeradbiomed.2010.10.696
  3. View record in Web of Science®
  4. WOS: 000286407700012

Library Notes

  1. Fiscal Year: FY2010-2011
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