A comparison of the antitumor effects of natural human tumor necrosis factors alpha and beta: the roles of arachidonic acid metabolism and intracellular cAMP.
We compared the antiproliferative efficacies of the natural human tumor necrosis factors alpha (nHuTNF-alpha) and beta (nHuTNF-beta). A phospholipase A2 inhibitor reduced the antitumor effects of both nHuTNF-alpha and nHuTNF-beta, but the inhibitory effect was more marked for nHuTNF-alpha than for nHuTNF-beta. Two other arachidonate metabolism pathways were also examined. A cyclo-oxygenase inhibitor moderately reduced nHuTNF-alpha-induced cell growth inhibition but did not affect nHuTNF-beta-induced growth inhibition, while a lipoxygenase inhibitor slightly reduced the antitumor effects of both types of nHuTNF. A third arachidonate metabolism pathway, cytochrome P450-dependent reductase inhibitor, did not affect nHuTNF-dependent growth inhibition. Exogenous cAMP and forskolin enhanced nHuTNF-alpha-induced growth inhibition but had no effect on nHuTNF-beta-induced growth inhibition. The stimulation of cancer cells by nHuTNF-alpha resulted in a significant elevation of intracellular cAMP concentrations, whereas nHuTNF-beta caused no such elevation. Additional studies demonstrated that combined nHuTNF-alpha and nHuTNF-beta (at similar unit concentrations, so that nHuTNF-beta was present at a molar concentration 1.4-fold greater than nHuTNF-alpha) showed an antitumor activity comparable to that of nHuTNF-alpha alone. These findings suggest the antiproliferative effect of nHuTNF-alpha to be both quantitatively and qualitatively distinguishable from that of nHuTNF-beta.
Shiiki
S
S
First Department of Surgery, Okayama University Medical School.
Fuchimoto
S
S
Orita
K
K
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008233:Lymphotoxin-alpha / Q000627:therapeutic use*; D008797:Metyrapone / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D054467:Phospholipases A2; D011796:Quinacrine / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
D001095:Arachidonic Acids; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D016718:Arachidonic Acid; D003907:Dexamethasone; D000242:Cyclic AMP; D010741:Phospholipases A; D054467:Phospholipases A2; D011796:Quinacrine; D007213:Indomethacin; D008797:Metyrapone