Mechanism of the anti-tumour effect of 2,3,5-trimethyl-6-(3-pyridylmethyl) 1,4-benzoquinone (CV-6504).
2,3,5-Trimethyl-6-(3-pyridylmethyl) 1,4-benzoquinone (CV-6504), an inhibitor of 5-lipoxygenase, effectively suppressed growth of the MAC16 tumour in vivo and prevented the accompanying cachexia, when administered daily at a dose of 10 mg kg(-1). There was a reduction in the tumour concentration of linoleic (LA), arachidonic (AA), oleic, stearic and palmitic acid. In order to elucidate the mechanism of the anti-tumour action, the effect of CV-6504 on the metabolism of AA through the 5-, 12- and 15-lipoxygenase pathways has been determined in cell lines sensitive (MAC16, MAC13, MAC26 and Caco-2) and resistant (A549 and DU-145) to CV-6504. Incubation of all cell lines with [3H]AA led to the appearance of [3H]5-, 12- and 15-HETE. Preincubation of MAC16, MAC13, MAC26 and Caco-2 with 10 microM CV-6504 inhibited the conversion of AA to 5-, 12- and 15-HETE, while in A549 and DU-145 cells there was no effect on metabolism through any lipoxygenase pathway. Two other cell lines, MDA-MB-231 and PC-3, sensitive to growth inhibition by CV-6504, are known to require LA for growth, while DU-145, which was insensitive to growth inhibition by CV-6504, showed no growth response to LA. These results suggest that some tumours are dependent on lipoxygenase metabolites of LA and AA for their continual growth, and interference with this pathway produces a specific growth inhibition.
Hussey
H J
HJ
Pharmaceutical Sciences Institute, Aston University, Birmingham, UK.
Tisdale
M J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology*; D002100:Cachexia / Q000517:prevention & control; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D051379:Mice; D008815:Mice, Inbred Strains; D019301:Oleic Acid / Q000378:metabolism; D019308:Palmitic Acid / Q000378:metabolism; D013229:Stearic Acids / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D017962:alpha-Linolenic Acid / Q000378:metabolism
D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D016227:Benzoquinones; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D013229:Stearic Acids; D017962:alpha-Linolenic Acid; C067513:CV 6504; D019301:Oleic Acid; D019308:Palmitic Acid; C031183:stearic acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid