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Open AccessArticle

Kinetics of Flavoenzyme-Catalyzed Reduction of Tirapazamine Derivatives: Implications for Their Prooxidant Cytotoxicity

1
State Research Institute Center for Innovative Medicine, Santariškių St. 5, LT-08406 Vilnius, Lithuania
2
Department of Xenobiotics Biochemistry, Institute of Biochemistry of Vilnius University, Saulėtekio 7, LT-10257 Vilnius, Lithuania
3
Department of Biochemistry and Molecular Biology, Institute of Biosciences of Vilnius University, Saulėtekio 7, LT-10257 Vilnius, Lithuania
4
Institute of Bioorganic Chemistry, NAS of Belarus, Kuprevicha 5/2, BY-220072 Minsk, Belarus
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(18), 4602; https://doi.org/10.3390/ijms20184602
Received: 6 August 2019 / Revised: 6 September 2019 / Accepted: 11 September 2019 / Published: 17 September 2019
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. View Full-Text
Keywords: tirapazamine; reductive activation; oxidative stress; cytotoxicity tirapazamine; reductive activation; oxidative stress; cytotoxicity
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Nemeikaitė-Čėnienė, A.; Šarlauskas, J.; Jonušienė, V.; Marozienė, A.; Misevičienė, L.; Yantsevich, A.V.; Čėnas, N. Kinetics of Flavoenzyme-Catalyzed Reduction of Tirapazamine Derivatives: Implications for Their Prooxidant Cytotoxicity. Int. J. Mol. Sci. 2019, 20, 4602.

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