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

Citation
P. Huang et al., Superoxide dismutase as a target for the selective killing of cancer cells, NATURE, 407(6802), 2000, pp. 390-395
Citations number
27
Categorie Soggetti
Multidisciplinary,Multidisciplinary,Multidisciplinary
Journal title
NATURE
ISSN journal
00280836 → ACNP
Volume
407
Issue
6802
Year of publication
2000
Pages
390 - 395
Database
ISI
SICI code
0028-0836(20000921)407:6802<390:SDAATF>2.0.ZU;2-4
Abstract
Superoxide dismutases (SOD) are essential enzymes that eliminate superoxide radical (O-2(-)) and thus protect cells from damage induced by free radica ls(1-3). The active O-2(-) production and low SOD activity in cancer cells( 3-7) may render the malignant cells highly dependent on SOD for survival an d sensitive to inhibition of SOD. Here we report that certain oestrogen der ivatives 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 a t the 2-carbon (2-OH, 2-OCH3) of the derivatives are essential for SOD inhi bition and for apoptosis induction. Inhibition of SOD causes accumulation o f cellular O-2(-) and leads to free-radical-mediated damage to mitochondria l membranes, the release of cytochrome c from mitochondria and apoptosis of the cancer cells. Our results indicate that targeting SOD may be a promisi ng approach to the selective killing of cancer cells, and that mechanism-ba sed combinations of SOD inhibitors with free-radical-producing agents may h ave clinical applications.