Effect of a hypoxic tumor cell cytotoxic disulfide on the membrane and DNA of tumor cells in culture.
A disulfide, n-butyl 2-imidazolyl disulfide (III-2), recently reported to be more toxic to EMT6 tumor cells under hypoxia has also been shown to be preferentially toxic to KHT/iv cells under hypoxia with an IC90 value 3-fold lower versus that measured in air. The IC90 values for both cell lines were markedly affected when the pHe was decreased. Uptake studies revealed that the disulfide is metabolized at the cell membrane with only one of the metabolites, n-butanethiol, being taken up into the cell. There were no differences in the amount of uptake under oxia or hypoxia. Investigation of potential membrane damage revealed that III-2 was a mixed inhibitor of the enzyme Na+,K(+)-ATPase, from isolated plasma membrane. DNA damage, when examined using plasmid DNA in the absence or presence of glutathione, was absent. Minor single-strand breaks to EMT6 DNA could only be observed following exposure to III-2 at the highest concentrations tested, with no differences observed between treatments in air or under hypoxia.
Kirkpatrick
D L
DL
Department of Chemistry, University of Regina, Saskatchewan, Canada.
King
K M
KM
Abu Sa'da
I
I
Kelln
R A
RA
Richardson
M E
ME
Siemann
D W
DW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects*; D004220:Disulfides / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000494:pharmacology*; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D010710:Phosphates / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D013056:Spectrophotometry, Ultraviolet; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004220:Disulfides; D007093:Imidazoles; D010710:Phosphates; C079762:n-butyl 2-imidazolyl disulfide; D000254:Sodium-Potassium-Exchanging ATPase