Cytotoxicity of anticancer aziridinyl-substituted benzoquinones in primary mice splenocytes.

Abstract

The anticancer activity of aziridinyl-quinones is mainly attributed to their NAD(P)H:quinone oxidoreductase 1 (NQO1)-catalyzed two-electron reduction into DNAalkylating products. However, little is known about their cytotoxicity in primary cells, which may be important in understanding their side effects. We found that the cytotoxicity of aziridinyl-unsubstituted quinones (n = 12) in mice splenocytes with a low amount of NQO1, 4 nmol × mg -1 × min -1 , was caused mainly by the oxidative stress. Aziridinyl-benzoquinones (n = 6) including a novel anticancer agent RH1 were more cytotoxic than aziridinylunsubstituted ones with the similar redox properties, and their cytotoxicity was not decreased by an inhibitor of NQO1, dicumarol. The possible reasons for their enhanced cytotoxicity are discussed.

QSARs in prooxidant mammalian cell cytotoxicity of nitroaromatic compounds: the roles of compound lipophilicity and cytochrome P-450- and DT-diaphorase-catalyzed reactions

“…However, the observed dependence of log cL 50 on E 1 7 may result from the superposition of oxidative stress and other cytotoxicity factors. The cytotoxicity of ArNO 2 lacking bioreductively activated groups was modulated by the inhibitors of flavoenzyme DT-diaphorase (NAD(P)H: quinone oxidoreductase, NQO1) and cytochromes P-450 [8,[11][12][13]. NQO1 performs two(four)-electron reduction of ArNO 2 into DNA-alkylating hydroxylamines (ArNHOH) ( [14,15], and references therein), and cytochromes P-450 catalyze the oxidative denitration of ArNO 2 [16,17].…”

“…However, it is unclear how do these processes contribute to cytotoxicity vs E 1 7 relationships. The data on the role of lipophilicity in the aerobic cytotoxicity of ArNO 2 are also equivocal [4,5,8,13,18]. This points to a need of more thorough characterization of the above factors.…”

Distinct activation mechanisms trigger the trypanocidal activity of DNA damaging prodrugs

“…major , with two compounds (RH1 and TZQ) exhibiting high potency (EC 50 values < 100 nM) against all three pathogens. However, this is accompanied by toxicity against macrophage (‐like) mammalian cells, a trait previously noted in primary mouse splenocytes (Miliukiene et al ., ). This unwanted activity may be because such immune cells have the ability to constitutively express or to upregulate quinone oxidoreductases including NQO1 and NQO1‐independent activities that promote oxidative stress and/or DNA damage (Tudor et al ., ; Potts‐Kant et al ., ; Miliukiene et al ., ).…”

“…However, this is accompanied by toxicity against macrophage (‐like) mammalian cells, a trait previously noted in primary mouse splenocytes (Miliukiene et al ., ). This unwanted activity may be because such immune cells have the ability to constitutively express or to upregulate quinone oxidoreductases including NQO1 and NQO1‐independent activities that promote oxidative stress and/or DNA damage (Tudor et al ., ; Potts‐Kant et al ., ; Miliukiene et al ., ). Although these cytotoxicity issues may preclude the use of these ABQs as therapies for the treatment of systemic infections, understanding how they mediate their trypanocidal activities can inform drug development.…”

Study of the cytotoxic effects of 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinone (MeDZQ) in mouse hepatoma cells

“…1)). Its redox properties, e.g., the single-electron reduction potential ( E 1 7 , or the redox potential of quinone/semiquinone couple, -0.23 V), and reactivity towards the main enzymes responsible for its single- and two-electron reduction, respectively, NADPH:cytochrome P-450 reductase and NQO1, are similar to those of its aziridinyl-unsubstituted analogue, tetramethyl-1,4-benzoquinone (duroquinone, DQ, E 1 7 = -0.26 V (Miliukiene et al, 2014[16])). …”