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.