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Abstract

The role of individual eicosanoids of the arachidonic acid (AA) cascade in the growth control of A549 human lung adenocarcinoma cells has been studied. Cyclooxygenase and lipoxygenase metabolites of [14C]AA incorporated were actively synthesized in the cultures of tumor cells with full confluence unaccomplished. In such cultures inhibitors of AA metabolism (indomethacin and esculetin) and also a lipoxygenase metabolite of AA, 15-hydroxyeicosatetraenoic acid (15-HETE), significantly suppressed the incorporation of [3H]thymidine and biosynthesis of prostaglandin E2 (PGE2). Other lipoxygenase metabolites of AA (5-HETE and 12-HETE) had no effect on these parameters. The basic fibroblast growth factor (bFGF) had practically no affect on the growth of A549 cells and the PGE2 production in cultures with 5% fetal calf serum (FCS); however, in the presence of 0.5% FCS this factor significantly increased the number of tumor cells. The growth-stimulating effect of bFGF was completely abolished by a cyclooxygenase inhibitor indomethacin. The data suggest a key role of PGE2 in the growth control of A549 cells with an active synthesis of cyclooxygenase and lipoxygenase metabolites of AA, its importance in realization of the mitogenic effect of bFGF, and specific features of 15-HETE as a down-regulator of the PGE2-dependent proliferation.

Lipoxygenase Pathway of Arachidonic Acid Metabolism in Growth Control of Tumor Cells of Different Type

“…On the first, second, and third day of the culture growth we introduced inhibitors of AA metabolism and/or different mono HETE. The concentration of used inhibitors was 10 -4 10 -6 M, the final concentration of 5 HETE, 12 HETE, and 15 HETE was 10 ng/ml, which is close to the con centration produced endogenously and pronouncedly modulates the growth of normal and tumor cells [11,22]. The effects of lipoxygenase metabolites of AA and inhibitors of eicosanoid biosynthesis on the cell prolifera tion at varied quantities of grown tumor cells were assessed on 48, 72, and 96 h of culture growth.…”

“…We studied biosynthesis of eicosanoids by tumor cells A549 under varied culture conditions earlier [11]. Lung adenocarci noma cells were characterized by a pronounced produc tion of cyclooxygenase and lipoxygenase metabolites of AA with a slight predominance of 5 HETE: 5 HETE > PGE 2 > PGF 2α > 15 HETE/12 HETE.…”

“…In the previous studies [11] 14 C]AA and the inhibitors with 0.5 ml of cell free homogenates of the lung tissue was performed at 37°C for 30 min. Spots with the corresponding eicosanoids were cut off from the chromatograms and extracted with methanol for subse quent radiometry.…”

“…The role of main lipoxygenase AA metabolites, different monohydroxy eicosatetraenoic acids (HETE), in the control of tumor cell growth is still unclear. Recent in vitro studies have revealed that one of these metabolites, 15 HETE, can inhibit PGE 2 dependent proliferation and considerably suppresses synthesis of DNA in some human tumor cells [11,12]. The ability to markedly stimulate the growth of a certain tumor cells was noted for another lipoxygenase AA metabolite, 5 HETE.…”

Principles of Nature

“…For the function with several variables, which is most often used in physical problems, the necessary condition of function extremum is that the function differential should equal zero [13] [14] [15]. The differentiated function f(P) = f(x 1 , •••, x n ) can reach the extremum only at a stationary point P 0 , i.е.…”