Inhibitors of lipoxygenase: a new class of cancer chemopreventive agents.
5-Lipoxygenase is a key enzyme in the metabolism of arachidonic acid to leukotrienes. The preventive efficacy of 5-lipoxygenase inhibitors against lung tumorigenesis was determined in A/J mice given the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in drinking water from week 0 to week +7. Groups of 25 mice were fed either: acetylsalicylic acid (ASA), a cyclooxygenase inhibitor; A-79175, a 5-lipoxygenase inhibitor; MK-886, an inhibitor of the 5-lipoxygenase activating-protein; a combination of ASA and A-79175 from weeks -2 to +23. ASA, A-79175 and MK-886 reduced lung tumor multiplicity by 44, 75 and 52% respectively. Furthermore, A-79175 reduced tumor incidence by 20%. Administration of A-79175 and MK-886 decreased the mean tumor volume by 64 and 44% respectively. Lung tumor multiplicity was directly proportional to tumor volume. The combination of ASA and A-79715 was the most effective preventive intervention and reduced lung tumor multiplicity by 87% and lung tumor incidence by 24%, demonstrating that inhibition of both 5-lipoxygenase and cyclooxygenase is more effective than inhibition of either pathway alone. NNK treatment increased plasma prostaglandin E2 levels from 49 to 260 pg/ml and plasma LTB4 levels from 29 to 71 pg/ml. Incubation of 82-132 and LM2 murine lung tumor cells with MK-886 and A-79715 decreased cell proliferation in a concentration-dependent manner. Soybean lipoxygenases with or without murine lung microsomal proteins metabolized NNK by alpha-carbon hydroxylation (9.5% of the metabolites) and N-oxidation (3.9%). Activation of NNK by alpha-carbon hydroxylation was inhibited by addition of arachidonic acid and A-79715. Possible mechanisms of action of 5-lipoxygenase inhibitors include inhibition of tumor growth and lipoxygenase-mediated activation of NNK. These studies suggest that inhibitors of 5-lipoxygenase may have benefits as preventive agents of lung tumorigenesis.
Rioux
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Laboratory of Cancer Etiology and Chemoprevention, Faculty of Pharmacy, Laval University, Quebec City, Canada.
Castonguay
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D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D016718:Arachidonic Acid / Q000378:metabolism; D001241:Aspirin / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use*; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008805:Mice, Inbred A; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control; D009602:Nitrosamines / Q000378:metabolism; D002722:Chlorobenzenes
D016588:Anticarcinogenic Agents; D016718:Arachidonic Acid; D001241:Aspirin; D002273:Carcinogens; D006918:Hydroxyurea; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D009602:Nitrosamines; C060893:MK-886; D002722:Chlorobenzenes; C082739:A 78773; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone