dinoprost and esculetin

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.

Topics: Adenocarcinoma; Arachidonic Acids; Carbon Radioisotopes; Cell Division; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; DNA; Fibroblast Growth Factor 2; Humans; Hydroxyeicosatetraenoic Acids; Indomethacin; Lung Neoplasms; Thymidine; Tritium; Tumor Cells, Cultured; Umbelliferones

Metastasis is a complex process, almost a cascade, involving multiple steps and activities. However, an important factor is that malignant cells are able to penetrate through the multiple basement membrane barriers surrounding tissues, blood vessels, nerves and muscle that would otherwise block their dissemination. Penetration of malignant tumor cells through basement membrane is an active process requiring proteolysis. We report here that inhibitors of both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism convert mouse melanoma and human fibrosarcoma cells to a non invasive state by reducing the production of MMP-2, an enzyme required for the degradation of basement membranes. Specific metabolites of each pathway, i.e. PGF2 alpha and 5-HPETE, are able to transcend the block and restore collagenase production, invasiveness in vitro and metastatic activity in vivo. These studies indicate a key role for arachidonic acid metabolites in metastasis and suggest novel therapeutic approaches for inhibiting the spread of cancer.

Topics: Animals; Arachidonic Acid; Caffeine; Collagen; Cyclooxygenase Inhibitors; Dinoprost; Drug Combinations; Extracellular Matrix; Fibrosarcoma; Gelatinases; Humans; Indoles; Indomethacin; Laminin; Leukotrienes; Lipoxygenase Inhibitors; Masoprocol; Matrix Metalloproteinase 2; Melanoma; Metalloendopeptidases; Mice; Neoplasm Metastasis; Proteoglycans; Tumor Cells, Cultured; Umbelliferones

The role of endogenously produced arachidonic acid metabolites on glomerulonephritis was investigated using cultured rat mesangial cells. The cultured mesangial cells could produce prostaglandin (PG) E2 and F2 alpha and 12-hydroxyeicosatetraenoic acid (12-HETE). The treatment of the mesangial cells with indomethacin enhanced the cell growth stimulated by 10% fetal calf serum (FCS). This stimulatory effect was significantly attenuated by concomitant treatment with PGE2, but not with PGF2 alpha. To test whether the mechanism by which PGE2 inhibited the mesangial cell growth is related to in the increment of cyclic AMP (cAMP), we examined the effect of dibutyryl cAMP on mesangial cell growth. As expected, treatment with dibutyryl cAMP decreased the cell proliferation. Moreover treatment with KT-5720, a protein kinase A (PKA) inhibitor, stimulated the cell growth as well as indomethacin. These data strongly suggest that the inhibition of mesangial cell growth by PGE2 involves an activation of PKA. In contrast, treatment with baicalein, a specific inhibitor of 12-lipoxygenase, inhibited the mesangial cell growth. The up and down regulations by arachidonic acid metabolites were also observed in the growth induced by platelet-derived growth factor (PDGF). These results suggest that endogenously produced arachidonic acid metabolites are involved in the regulation of mesangial cell growth.

Topics: 1-Methyl-3-isobutylxanthine; 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Arachidonic Acid; Benzeneacetamides; Bucladesine; Carbazoles; Cell Division; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dinoprost; Dinoprostone; DNA Replication; Flavanones; Flavonoids; Glomerular Mesangium; Hydroxamic Acids; Hydroxyeicosatetraenoic Acids; Indoles; Indomethacin; Lipoxygenase Inhibitors; Male; Platelet-Derived Growth Factor; Pyrroles; Rats; Rats, Sprague-Dawley; Umbelliferones