Aerobic Cytotoxicity of Aromatic N-Oxides: The Role of NAD(P)H:Quinone Oxidoreductase (NQO1)

Derivatives of tirapazamine and other heteroaromatic N-oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities, which are typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the role of NAD(P)H:quinone oxidoreductase (NQO1) in ArN→O aerobic cytotoxicity. We synthesized 9 representatives of ArN→O with uncharacterized redox properties and examined their single-electron reduction by rat NADPH:cytochrome P-450 reductase (P-450R) and Plasmodium falciparum ferredoxin:NADP+ oxidoreductase (PfFNR), and by rat NQO1. NQO1 catalyzed both redox cycling and the formation of stable reduction products of ArN→O. The reactivity of ArN→O in NQO1-catalyzed reactions did not correlate with the geometric average of their activity towards P-450R- and PfFNR, which was taken for the parameter of their redox cycling efficacy. The cytotoxicity of compounds in murine hepatoma MH22a cells was decreased by antioxidants and the inhibitor of NQO1, dicoumarol. The multiparameter regression analysis of the data of this and a previous study (DOI: 10.3390/ijms20184602) shows that the cytotoxicity of ArN→O (n = 18) in MH22a and human colon carcinoma HCT-116 cells increases with the geometric average of their reactivity towards P-450R and PfFNR, and with their reactivity towards NQO1. These data demonstrate that NQO1 is a potentially important target of action of heteroaromatic N-oxides.

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

International Journal of Molecular Sciences ◽

10.3390/ijms20184602 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4602 ◽

Cited By ~ 4

Author(s):

Nemeikaitė-Čėnienė ◽

Šarlauskas ◽

Jonušienė ◽

Marozienė ◽

Misevičienė ◽

...

Keyword(s):

Colon Adenocarcinoma ◽

Human Colon ◽

Single Electron ◽

Reductive Activation ◽

Midpoint Potential ◽

Cell Compartments ◽

Hct 116 ◽

Electron Reduction ◽

Hct 116 Cells ◽

Adrenodoxin Reductase

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.

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Synthesis, Characterization, and Cytotoxicity of Binuclear Cooper(II)-Complexes with some S-Alkenyl Derivatives of Thiosalicyclic Acid

Serbian Journal of Experimental and Clinical Research ◽

10.1515/sjecr-2016-0071 ◽

2017 ◽

Vol 18 (1) ◽

pp. 13-18 ◽

Cited By ~ 2

Author(s):

Dusan Lj. Tomovic ◽

Andriana M. Bukonjic ◽

Aleksandar Kocovic ◽

Milos V. Nikolic ◽

Marina Z. Mijajlovic ◽

...

Keyword(s):

Cytotoxic Effect ◽

Magnetic Measurements ◽

Human Colon ◽

Carcinoma Cells ◽

Thiosalicylic Acid ◽

Colon Carcinoma Cells ◽

Human Colon Carcinoma ◽

Hct 116 ◽

Hct 116 Cells ◽

Derivatives Of

Abstract New complexes of copper(II) with S-alkenyl derivatives of thiosalicylic acid (alkenyl = propenyl-(L1), isobutenyl-(L2)) have been synthesized and characterized by microanalysis, infrared spectra, magnetic measurements, and by NMR spectra. The cytotoxic activity of two newly synthesized precursor S-alkenyl derivatives of thiosalicylic acid were tested using an MTT colorimetric technique on HCT-116 human colon carcinoma cells. The cytotoxic effect of the copper(II)- complexes were higher compared to the cytotoxicity of the corresponding ligand (for concentrations from 31.25 to 250 μM). Copper(II)-complexes showed a slightly lower cytotoxicity compared to cisplatin. Complexes of copper(II) with S-alkenyl derivatives of thiosalicylic acid (at concentrations from 250 to 1000 μM) had a cytotoxic effect on HCT-116 cells compared to cisplatin.

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Role of NAD(P)H:quinone oxidoreductase (NQO1) in apoptosis induction by aziridinylbenzoquinones RH1 and MeDZQ.

Acta Biochimica Polonica ◽

10.18388/abp.2005_3411 ◽

2005 ◽

Vol 52 (4) ◽

pp. 937-942 ◽

Cited By ~ 4

Author(s):

Ausra Nemeikaite-Ceniene ◽

Aldona Dringeliene ◽

Jonas Sarlauskas ◽

Narimantas Cenas

Keyword(s):

Regression Analysis ◽

Redox Cycling ◽

Apoptosis Induction ◽

Electron Reduction ◽

Induced Apoptosis ◽

Phenylene Diamine

We aimed to characterize the role of NAD(P)H:quinone oxidoreductase (NQO1) in apoptosis induction by antitumour quinones RH1 (2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone) and MeDZQ (2,5-dimethyl-3,6-diaziridinyl-1,4-benzoquinone). Digitonin-permeabilized FLK cells catalyzed NADPH-dependent single- and two-electron reduction of RH1 and MeDZQ. At equitoxic concentrations, RH1 and MeDZQ induced apoptosis more efficiently than the nonalkylating duroquinone or H(2)O(2). The antioxidant N,N'-diphenyl-p-phenylene diamine, desferrioxamine, and the inhibitor of NQO1 dicumarol, protected against apoptosis induction by all compounds investigated, but to a different extent. The results of multiparameter regression analysis indicate that RH1 and MeDZQ most likely induce apoptosis via NQO1-linked formation of alkylating species but not via NQO1-linked redox cycling.

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Cytotoxic property of ultraviolet-induced rice phytoalexins to human colon carcinoma HCT-116 cells

Journal of the Korean Society for Applied Biological Chemistry ◽

10.1007/s13765-012-3238-3 ◽

2013 ◽

Vol 56 (2) ◽

pp. 237-241 ◽

Cited By ~ 7

Author(s):

Jong-Hwa Park ◽

Yuan-Yuan Fu ◽

In Sik Chung ◽

Tae-Ryong Hahn ◽

Man-Ho Cho

Keyword(s):

Colon Carcinoma ◽

Human Colon ◽

Cytotoxic Property ◽

Human Colon Carcinoma ◽

Hct 116 ◽

Hct 116 Cells

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KT2 and RT2 modified antimicrobial peptides derived from Crocodylus siamensis Leucrocin I show activity against human colon cancer HCT-116 cells

Environmental Toxicology and Pharmacology ◽

10.1016/j.etap.2018.07.007 ◽

2018 ◽

Vol 62 ◽

pp. 164-176 ◽

Cited By ~ 6

Author(s):

Surachai Maijaroen ◽

Nisachon Jangpromma ◽

Jureerut Daduang ◽

Sompong Klaynongsruang

Keyword(s):

Colon Cancer ◽

Antimicrobial Peptides ◽

Human Colon ◽

Human Colon Cancer ◽

Hct 116 ◽

Crocodylus Siamensis ◽

Hct 116 Cells

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Role of P53, Bax, P21, and DNA PKcs in Radiation Sensitivity of HCT-116 Cells

Journal of Surgical Research ◽

10.1016/j.jss.2012.10.192 ◽

2013 ◽

Vol 179 (2) ◽

pp. 192

Author(s):

S. Huerta ◽

X. Gao ◽

S.P. Dineen ◽

P. Kapur ◽

D. Saha ◽

...

Keyword(s):

Radiation Sensitivity ◽

Hct 116 ◽

Hct 116 Cells

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Development and Characterization of a Model of Liver Metastasis Using Human Colon Cancer HCT-116 Cells

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.30.1779 ◽

2007 ◽

Vol 30 (9) ◽

pp. 1779-1783 ◽

Cited By ~ 30

Author(s):

Kazuhiro Ishizu ◽

Naohide Sunose ◽

Kanami Yamazaki ◽

Takashi Tsuruo ◽

Sotaro Sadahiro ◽

...

Keyword(s):

Colon Cancer ◽

Liver Metastasis ◽

Human Colon ◽

Human Colon Cancer ◽

Hct 116 ◽

Hct 116 Cells

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The Induction of Apoptosis by Resveratrol Through Regulatory Effect of miR-21 on the Gene Expression of Bcl2 and Bax in HCT-116 Cells

Avicenna Journal of Medical Biochemistry ◽

10.34172/ajmb.2019.05 ◽

2019 ◽

Vol 7 (1) ◽

pp. 21-27

Author(s):

Nooshin Shabab ◽

Saeid Afshar ◽

Massoud Saidijam

Keyword(s):

Gene Expression ◽

Vital Role ◽

Expression Level ◽

Apoptosis Pathway ◽

Treatment Agent ◽

Hct 116 ◽

Pcr Method ◽

Hct 116 Cells

Background: Resveratrol (RezV) which is found in several plants including grapes and types of berries has a vital role in inducing apoptosis and suppressing cell proliferation. Although the role of Bcl-2 in the apoptosis has been known in several pathways, the role and mechanism of miR-21 in the regulation of apoptosis in colorectal cancer (CRC) cells are unclear. Objectives: The main aim of this study was to evaluate the effects of RezV on the expression level of miR-21, Bax, and Bcl2 in colorectal tumor cells. Methods: In this study, the effect of RezV on the viability of CRC cells was evaluated by MTT assay. Then, the expression level of miR-21 was evaluated by real-time polymerase chain reaction (PCR) method. For evaluating HCT-116 cells apoptosis, the expression level of Bax and Bcl2 that are involved in the apoptosis pathway was investigated by the same method. Results: RezV inhibits the viability of HCT-116 cells. MiR-21 gene expression was decreased after 24 hours of treatment with RezV. The reduction of miR-21 expression leads to the reduction of the Bcl2 gene expression level. Moreover, increasing the Bax/Bcl2 ratio enhances HCT-116 cells apoptosis. Conclusion: In summary, RezV might be used as a co-treatment agent for CRC. On the other hand, conducting the in vivo study to evaluate the effects of RezV was critical.

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