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Superoxide dismutase as a target for the selective killing of cancer cells

Nature volume 407, pages 390395 (21 September 2000) | Download Citation

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Abstract

Superoxide dismutases (SOD) are essential enzymes that eliminate superoxide radical (O2-) and thus protect cells from damage induced by free radicals1,2,3. The active O2 - production and low SOD activity in cancer cells3,4,5,6,7 may render the malignant cells highly dependent on SOD for survival and sensitive to inhibition of SOD. Here we report that certain oestrogen derivatives selectively kill human leukaemia cells but not normal lymphocytes. Using complementary DNA microarray and biochemical approaches, we identify SOD as a target of this drug action and show that chemical modifications at the 2-carbon (2-OH, 2-OCH3) of the derivatives are essential for SOD inhibition and for apoptosis induction. Inhibition of SOD causes accumulation of cellular O2- and leads to free-radical-mediated damage to mitochondrial membranes, the release of cytochrome c from mitochondria and apoptosis of the cancer cells. Our results indicate that targeting SOD may be a promising approach to the selective killing of cancer cells, and that mechanism-based combinations of SOD inhibitors with free-radical-producing agents may have clinical applications.

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Acknowledgements

We thank J. Engelhardt and the Vector Core Facility of University of Iowa for Ad.CuZnSOD, Ad.MnSOD and the control viral vectors; M. Du and A. Sandoval for technical assistance in the isolation and preparation of primary cells from health donors and from leukaemia patients; and J. Richard for editorial assistance. This work was supported in part by NIH/NCI grants to P.H. and W.P.

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  1. *Department of Experimental Therapeutics,

    • Peng Huang
    • , Li Feng
    • , Elizabeth A. Oldham
    •  & William Plunkett
  2. †Department of Leukaemia, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA

    • Michael J. Keating

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Correspondence to Peng Huang.

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https://doi.org/10.1038/35030140

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