Caffeine, aminoimidazolecarboxamide and dicoumarol, inhibitors of NAD(P)H dehydrogenase (quinone) (DT diaphorase), prevent both the cytotoxicity and DNA interstrand crosslinking produced by 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) in Walker cells.
A form of NAD(P)H dehydrogenase (quinone) (DT diaphorase, menadione reductase (NMOR), phylloquinone reductase, quinone reductase, EC 1.6.99.2) has been isolated from Walker 256 rat carcinoma cells. This enzyme can convert 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) to a cytotoxic DNA interstrand crosslinking agent by reduction of its 4-nitro group to the corresponding hydroxylamino species (Knox et al. Biochem Pharmacol, 37: 4661-4669 and 4671-4677, 1988). 2-Phenyl-5(4)-aminoimidazole-4(5)-carboxamide and AICA [5(4)-aminoimidazole-4(5)-carboxamide] have previously been reported to be antagonists of the anti-tumour effects of CB 1954. We have shown that both these compounds are inhibitors of the above enzyme and that AICA protects against both the cytotoxicity and the formation of DNA interstrand crosslinks, produced by CB 1954 in Walker cells. Similarly, known inhibitors of NAD(P)H dehydrogenase (quinone) such as dicoumarol, also reduced the cytotoxicity and DNA-interstrand crosslinking of CB 1954 in Walker cells. Caffeine was shown to be a novel inhibitor of NAD(P)H dehydrogenase (quinone) and also elicited the above protective effects. All of the above inhibitors were also shown to potentiate the toxic effects of menadione against the Walker cell. This quinone is known to be detoxified by NAD(P)H dehydrogenase (quinone) and thus emphasises the ability of these compounds to inhibit this enzyme within the cell.
Roberts
J J
JJ
Section of Drug Development, Institute of Cancer Research, Sutton, Surrey, U.K.
Marchbank
T
T
Kotsaki-Kovatsi
V P
VP
Boland
M P
MP
Friedlos
F
F
Knox
R J
RJ
D000620:Aminoimidazole Carboxamide / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001388:Aziridines / Q000378:metabolism / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology; D003432:Cross-Linking Reagents; D004247:DNA / Q000378:metabolism*; D001728:Dicumarol / Q000494:pharmacology; D004357:Drug Synergism; D016660:NAD(P)H Dehydrogenase (Quinone); D009374:Neoplasms, Experimental / Q000378:metabolism*; D011808:Quinone Reductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D014407:Tumor Cells, Cultured; D014812:Vitamin K / Q000494:pharmacology
D000970:Antineoplastic Agents; D001388:Aziridines; D003432:Cross-Linking Reagents; D014812:Vitamin K; D000620:Aminoimidazole Carboxamide; D002110:Caffeine; C100099:tretazicar; D001728:Dicumarol; D004247:DNA; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases