Role of redox cycling and activation by DT-diaphorase in the cytotoxicity of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB-1954) and its analogs

In tumor cell lines with high content of DT-diaphorase (EC 1.6.99.2), the cytotoxicity of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB-1954) and its derivatives is exerted through DT-diaphorase-catalyzed formation of crosslinking species. However, little is known about other possible mechanisms of CB-1954 action. We have examined the toxicity of CB-1954 and its derivatives to bovine leukemia virus-transformed lamb fibroblasts (line FLK), which possessed moderate DT-diaphorase activity, 260 units/mg protein. The action of these compounds was accompanied by lipid peroxidation, their toxicity was decreased by desferrioxamine and antioxidant N,N′-diphenyl-p-phenylene diamine (DPPD), but, in most cases, not by dicumarol, an inhibitor of DT-diaphorase. Using multiparameter regression analysis, we have found that the toxicity of CB-1954 derivatives as well as that of several non-alkylating nitroaromatics, increased upon the increase in their single-electron reduction potential (E17) and octanol/water partition coefficient (P), and almost did not depend on their reactivity towards DT-diaphorase. It seems that in cell lines with a moderate amount of DT-diaphorase, the toxicity of CB-1954 and its analogs is exerted through their redox cycling.