Inhibition of DT-diaphorase (NAD(P)H:quinone oxidoreductase, EC 1.6.99.2) by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone-8-acetic acid (FAA)

implications for bioreductive drug development

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The tumour blood flow inhibitors 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone-8-acetic acid (FAA) have been shown to potentiate the antitumour activity of several bioreductive drugs in vivo. Whilst the induction of hypoxia as a result of blood flow inhibition is presumed to be responsible for enhancing the activity of bioreductive drugs, no studies have examined potential interactions between DMXAA or FAA and enzymes involved in bioreductive drug activation. Both FAA and DMXAA are competitive inhibitors of the enzyme DT-diaphorase (NAD(P)H:Quinone oxidoreductase EC 1.6.99.2) with respect to NADH, with Ki values of 75 and 20 microM, respectively. Cytochromes P450 reductase and b5 reductase activities are not significantly inhibited by FAA, whereas DMXAA partially inhibits cytochrome b5 reductase activity. The cytotoxicity of the indoloquinone EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione] prop-beta-en-alpha-ol) against DLD-1 (IC50 = 0.32+/-0.08 microM) was significantly reduced when combinations of EO9 and FAA (IC50 = 12.26+/-5.43 microM) or DMXAA (IC50 > 40 microM) were used. In the case of menadione (which is detoxified by DT-diaphorase), combinations of menadione with FAA or DMXAA were more toxic (IC50 = 7.46+/-2.22 and 9.46+/-1.70 microM, respectively) than menadione alone (IC50 = 22.02+/-1.59 microM). Neither DMXAA nor FAA potentiated the activity of tirapazamine in vitro. These results suggest that the use of DMXAA and FAA to potentiate the activity of bioreductive drugs where DT-diaphorase plays a central role in either activation or detoxification may be inappropriate. The fact that FAA in particular does not inhibit other key enzymes involved in bioreductive activation suggests that it may be useful in terms of identifying DT-diaphorase-activated prodrugs.

Original languageEnglish
Pages (from-to)303-310
Number of pages8
JournalBiochemical Pharmacology
Volume58
Issue number2
DOIs
Publication statusPublished - 15 Jul 1999
Externally publishedYes

Fingerprint

vadimezan
flavone acetic acid
NAD(P)H Dehydrogenase (Quinone)
NAD
Oxidoreductases
apaziquone
Inhibitory Concentration 50
Pharmaceutical Preparations
Vitamin K 3
Cytochromes b5
tirapazamine
Chemical activation
Indolequinones
Blood
Cytochrome Reductases
benzoquinone
NADPH-Ferrihemoprotein Reductase
Detoxification
Poisons
Prodrugs

Cite this

@article{d97ef2fe1cd040978a199dd173f3077b,
title = "Inhibition of DT-diaphorase (NAD(P)H:quinone oxidoreductase, EC 1.6.99.2) by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone-8-acetic acid (FAA): implications for bioreductive drug development",
abstract = "The tumour blood flow inhibitors 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone-8-acetic acid (FAA) have been shown to potentiate the antitumour activity of several bioreductive drugs in vivo. Whilst the induction of hypoxia as a result of blood flow inhibition is presumed to be responsible for enhancing the activity of bioreductive drugs, no studies have examined potential interactions between DMXAA or FAA and enzymes involved in bioreductive drug activation. Both FAA and DMXAA are competitive inhibitors of the enzyme DT-diaphorase (NAD(P)H:Quinone oxidoreductase EC 1.6.99.2) with respect to NADH, with Ki values of 75 and 20 microM, respectively. Cytochromes P450 reductase and b5 reductase activities are not significantly inhibited by FAA, whereas DMXAA partially inhibits cytochrome b5 reductase activity. The cytotoxicity of the indoloquinone EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione] prop-beta-en-alpha-ol) against DLD-1 (IC50 = 0.32+/-0.08 microM) was significantly reduced when combinations of EO9 and FAA (IC50 = 12.26+/-5.43 microM) or DMXAA (IC50 > 40 microM) were used. In the case of menadione (which is detoxified by DT-diaphorase), combinations of menadione with FAA or DMXAA were more toxic (IC50 = 7.46+/-2.22 and 9.46+/-1.70 microM, respectively) than menadione alone (IC50 = 22.02+/-1.59 microM). Neither DMXAA nor FAA potentiated the activity of tirapazamine in vitro. These results suggest that the use of DMXAA and FAA to potentiate the activity of bioreductive drugs where DT-diaphorase plays a central role in either activation or detoxification may be inappropriate. The fact that FAA in particular does not inhibit other key enzymes involved in bioreductive activation suggests that it may be useful in terms of identifying DT-diaphorase-activated prodrugs.",
keywords = "Antineoplastic Agents/pharmacology, Aziridines/pharmacology, Cell Survival/drug effects, Cytochrome Reductases/antagonists & inhibitors, Cytochrome-B(5) Reductase, Enzyme Inhibitors/pharmacology, Flavonoids/pharmacology, Humans, Indolequinones, Indoles/pharmacology, NAD(P)H Dehydrogenase (Quinone)/antagonists & inhibitors, NADPH-Ferrihemoprotein Reductase/antagonists & inhibitors, Triazines/pharmacology, Tumor Cells, Cultured, Vitamin K/pharmacology, Xanthenes/pharmacology, Xanthones",
author = "Phillips, {R M}",
year = "1999",
month = "7",
day = "15",
doi = "10.1016/S0006-2952(99)00092-1",
language = "English",
volume = "58",
pages = "303--310",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "2",

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TY - JOUR

T1 - Inhibition of DT-diaphorase (NAD(P)H:quinone oxidoreductase, EC 1.6.99.2) by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone-8-acetic acid (FAA)

T2 - implications for bioreductive drug development

AU - Phillips, R M

PY - 1999/7/15

Y1 - 1999/7/15

N2 - The tumour blood flow inhibitors 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone-8-acetic acid (FAA) have been shown to potentiate the antitumour activity of several bioreductive drugs in vivo. Whilst the induction of hypoxia as a result of blood flow inhibition is presumed to be responsible for enhancing the activity of bioreductive drugs, no studies have examined potential interactions between DMXAA or FAA and enzymes involved in bioreductive drug activation. Both FAA and DMXAA are competitive inhibitors of the enzyme DT-diaphorase (NAD(P)H:Quinone oxidoreductase EC 1.6.99.2) with respect to NADH, with Ki values of 75 and 20 microM, respectively. Cytochromes P450 reductase and b5 reductase activities are not significantly inhibited by FAA, whereas DMXAA partially inhibits cytochrome b5 reductase activity. The cytotoxicity of the indoloquinone EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione] prop-beta-en-alpha-ol) against DLD-1 (IC50 = 0.32+/-0.08 microM) was significantly reduced when combinations of EO9 and FAA (IC50 = 12.26+/-5.43 microM) or DMXAA (IC50 > 40 microM) were used. In the case of menadione (which is detoxified by DT-diaphorase), combinations of menadione with FAA or DMXAA were more toxic (IC50 = 7.46+/-2.22 and 9.46+/-1.70 microM, respectively) than menadione alone (IC50 = 22.02+/-1.59 microM). Neither DMXAA nor FAA potentiated the activity of tirapazamine in vitro. These results suggest that the use of DMXAA and FAA to potentiate the activity of bioreductive drugs where DT-diaphorase plays a central role in either activation or detoxification may be inappropriate. The fact that FAA in particular does not inhibit other key enzymes involved in bioreductive activation suggests that it may be useful in terms of identifying DT-diaphorase-activated prodrugs.

AB - The tumour blood flow inhibitors 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone-8-acetic acid (FAA) have been shown to potentiate the antitumour activity of several bioreductive drugs in vivo. Whilst the induction of hypoxia as a result of blood flow inhibition is presumed to be responsible for enhancing the activity of bioreductive drugs, no studies have examined potential interactions between DMXAA or FAA and enzymes involved in bioreductive drug activation. Both FAA and DMXAA are competitive inhibitors of the enzyme DT-diaphorase (NAD(P)H:Quinone oxidoreductase EC 1.6.99.2) with respect to NADH, with Ki values of 75 and 20 microM, respectively. Cytochromes P450 reductase and b5 reductase activities are not significantly inhibited by FAA, whereas DMXAA partially inhibits cytochrome b5 reductase activity. The cytotoxicity of the indoloquinone EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione] prop-beta-en-alpha-ol) against DLD-1 (IC50 = 0.32+/-0.08 microM) was significantly reduced when combinations of EO9 and FAA (IC50 = 12.26+/-5.43 microM) or DMXAA (IC50 > 40 microM) were used. In the case of menadione (which is detoxified by DT-diaphorase), combinations of menadione with FAA or DMXAA were more toxic (IC50 = 7.46+/-2.22 and 9.46+/-1.70 microM, respectively) than menadione alone (IC50 = 22.02+/-1.59 microM). Neither DMXAA nor FAA potentiated the activity of tirapazamine in vitro. These results suggest that the use of DMXAA and FAA to potentiate the activity of bioreductive drugs where DT-diaphorase plays a central role in either activation or detoxification may be inappropriate. The fact that FAA in particular does not inhibit other key enzymes involved in bioreductive activation suggests that it may be useful in terms of identifying DT-diaphorase-activated prodrugs.

KW - Antineoplastic Agents/pharmacology

KW - Aziridines/pharmacology

KW - Cell Survival/drug effects

KW - Cytochrome Reductases/antagonists & inhibitors

KW - Cytochrome-B(5) Reductase

KW - Enzyme Inhibitors/pharmacology

KW - Flavonoids/pharmacology

KW - Humans

KW - Indolequinones

KW - Indoles/pharmacology

KW - NAD(P)H Dehydrogenase (Quinone)/antagonists & inhibitors

KW - NADPH-Ferrihemoprotein Reductase/antagonists & inhibitors

KW - Triazines/pharmacology

KW - Tumor Cells, Cultured

KW - Vitamin K/pharmacology

KW - Xanthenes/pharmacology

KW - Xanthones

U2 - 10.1016/S0006-2952(99)00092-1

DO - 10.1016/S0006-2952(99)00092-1

M3 - Article

VL - 58

SP - 303

EP - 310

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 2

ER -