Abstract
Derivatives of tirapazamine and other heteroaromatic N-oxides (ArN→O) exhibit promising antibacterial, antiprotozoal, and tumoricidal activities. Their action is typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the mechanism(s) of aerobic mammalian cell cytotoxicity of ArN→O performing the parallel studies of their reactions with NADPH:cytochrome P-450 reductase (P-450R), adrenodoxin reductase/adrenodoxin (ADR/ADX), and NAD(P)H:quinone oxidoreductase (NQO1); we found that in P-450R and ADR/ADX-catalyzed single-electron reduction, the reactivity of ArN→O (n = 9) increased with their single-electron reduction midpoint potential (E17), and correlated with the reactivity of quinones. NQO1 reduced ArN→O at low rates with concomitant superoxide production. The cytotoxicity of ArN→O in murine hepatoma MH22a and human colon adenocarcinoma HCT-116 cells increased with their E17, being systematically higher than that of quinones. The cytotoxicity of both groups of compounds was prooxidant. Inhibitor of NQO1, dicoumarol, and inhibitors of cytochromes P-450 α-naphthoflavone, isoniazid and miconazole statistically significantly (p < 0.02) decreased the toxicity of ArN→O, and potentiated the cytotoxicity of quinones. One may conclude that in spite of similar enzymatic redox cycling rates, the cytotoxicity of ArN→O is higher than that of quinones. This is partly attributed to ArN→O activation by NQO1 and cytochromes P-450. A possible additional factor in the aerobic cytotoxicity of ArN→O is their reductive activation in oxygen-poor cell compartments, leading to the formation of DNA-damaging species similar to those forming under hypoxia.
Highlights
N-oxides of 1,2,4-benzotriazine and quinoxaline (ArN→O) frequently possess promising antibacterial, antiprotozoal, and tumoricidal activities, including their potential application in the treatment of hypoxic tumors ([1,2], and references therein)
The aim of this work was to characterize the relation between the aerobic cytotoxicity of TPZ derivatives and their reactivity towards single-electron transferring P-450 reductase (P-450R), and another model system, adrenodoxin reductase/adrenodoxin (ADR/ADX)
Taken together with further cytotoxicity studies, it revealed that the cytotoxicity of ArN→O was higher than that of quinones with similar redox properties. We found that this phenomenon is partly attributed to the action of NQO1 and P-450
Summary
N-oxides of 1,2,4-benzotriazine and quinoxaline (ArN→O) frequently possess promising antibacterial, antiprotozoal, and tumoricidal activities, including their potential application in the treatment of hypoxic tumors ([1,2], and references therein). In most cases, their action is attributed to bioreductive activation and free radical generation. Their action is attributed to bioreductive activation and free radical generation Among their representatives, the redox reactions of 3-amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ) and its derivatives have been studied most comprehensively.
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