Oxidative stress induced by a copper-thiosemicarbazone complex.
Copper thiosemicarbazones cause considerable oxidative stress. This effect may be related to their cytotoxicity. In the present work, the chemical and cellular properties of a new ligand, pyridoxal thiosemicarbazone (H2T), and its copper(II) chelate (CuT) are assessed. CuT is toxic to cultured Ehrlich ascites tumor cells, producing nearly complete cell kill at drug/cell ratios of 2.5-4 nmol/10(5) cells in a monolayer culture over a 48-h treatment period. This concentration is at least 1 order of magnitude lower than those required for a similar degree of cytotoxicity by H2T or CuCl2. The following observations support the view that activated oxygen species are generated by interaction of CuT with Ehrlich cells: (1) Room-temperature electron spin resonance spectroscopy and atomic absorption measurements show rapid cellular uptake and CuT-thiol adduct formation. (2) Cellular thiol content is reduced. (3) High levels of DNA strand scission result from 1-h treatments of cells by concentrations of CuT that cause growth inhibition and toxicity. (4) The extent of strand scission can be increased by addition of superoxide dismutase and decreased by catalase or DMSO in the treatment medium. Catalase and DMSO do not inhibit the toxic effect of CuT. This suggests that DNA damage is not responsible for inhibition of cell proliferation by CuT.
Byrnes
R W
RW
Department of Chemistry, University of Wisconsin, Milwaukee 53201.
Mohan
M
M
Antholine
W E
WE
Xu
R X
RX
Petering
D H
DH
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000187:drug effects; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D005978:Glutathione; D009942:Organometallic Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D010084:Oxidation-Reduction; D013053:Spectrophotometry; D013882:Thiosemicarbazones / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D004277:DNA, Single-Stranded; D005609:Free Radicals; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; C066363:copper-thiosemicarbazone complex; D005978:Glutathione