Regulation of proliferation of rat mammary tumor cells by inhibitors of cyclooxygenase and lipoxygenase.
The studies described herein were undertaken with the objective of determining the effect of modulation of arachidonic acid metabolism on proliferation of rat mammary tumor cells in culture. The TMT-081 rat mammary tumor cell line was shown to metabolize [14C]arachidonic acid to thromboxane B2, PGE2, PGF2 alpha, and 12- and/or 15-HETE. Furthermore, synthesis of these eicosanoids was physiologically significant since each metabolite stimulated DNA synthesis. Both cyclooxygenase and lipoxygenase inhibitors suppressed cell growth and modulated eicosanoid synthesis in a concentration-dependent manner. Thin layer chromatography showed that the production of cyclooxygenase metabolites (thromboxane B2, PGE2 and PGF2 alpha) by TMT-081 cells was inhibited by indomethacin, ibuprofen, BW755C and timegadine. The lipoxygenase inhibitor NDGA was also shown to inhibit thromboxane B2 synthesis, but increased PGE2 and PGF2 alpha syntheses; esculetin, a lipoxygenase inhibitor in other systems, increased all the cyclooxygenase products. The production of the lipoxygenase products 12- and/or 15-HETE was inhibited by NDGA, increased by indomethacin and ibuprofen, but not affected by esculetin, BW755C and timegadine in this cell line. Changes in eicosanoid profile were observed before drug-induced inhibition of cell growth suggesting that the balance of the various eicosanoids may be a critical determinant of cell proliferation. However, since drug-induced effects on arachidonic acid profile occurred at concentrations lower than that necessary for inhibition of cell growth, the effects of these inhibitors on other biochemical pathways affecting cell growth cannot be ruled out.
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Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263.
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D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D015777:Eicosanoids / Q000378:metabolism / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
D016861:Cyclooxygenase Inhibitors; D004273:DNA, Neoplasm; D015777:Eicosanoids; D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid