SUPPRESSION OF TUMOR PROMOTER-INDUCED CHEMI-LUMINESCENCE IN MOUSE EPIDERMAL-CELLS BY SEVERAL INHIBITORS OF ARACHIDONIC-ACID METABOLISM

  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (7) , 3130-3136
Abstract
The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is a stimulator of chemiluminescence (CL) in SENCAR mouse epidermal cells. The CL response is TPA dose-dependent (8 to 800 nM) as well as proportional to the number of cells used. Treatment with 166 nM TPA results in a CL response that peaks by 15 min although a strong response persists for over 30 min. The CL response can be inhibited by superoxide dismutase and the superoxide dismutase mimetic Cu(II) (3,4 diisopropylsalicyclic acid)2, suggesting that the CL response may be due to or mediated by superoxide anions. Catalase, which is specific for H2O2 and mannitol, which is a scavenger for hydroxyl radicals, had negligible inhibitory effects. The CL response is also inhibited by retinoic acid and the analog ethyl all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate. A series of phorbol esters with different promoting abilities produced corresponding CL responses. The 2nd stage tumor promoter mezerein is as effective as TPA in stimulating CL. Inhibitors of various parts of the arachidonic acid cascade were found to affect the TPA-induced CL response in a manner that corresponds to their effects in in vivo tumor promotion experiments: agents which are predominantly lipoxygenase inhibitors, i.e., nordihydroguaiaretic acid, benoxaprofen or agents which are effective against both lipoxygenase or cyclooxygenase, i.e., 5,8,11,14-eicosatetraenoic acid and phenidone, are effective in diminishing the CL response. Cyclooxygenase inhibitors, i.e., indomethacin and flurbiprofen, have no or a slight enhancing effect at low doses. At least a major part of the TPA-induced CL response is due to the metabolism of arachidonic acid, most probably by the lipoxygenase(s). This CL assay may provide a useful system for studying the involvement of oxidants in tumor promotion.

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