Evidence that endogenous generation of leukotrienes does not regulate proliferation of malignant hemopoietic cell lines

• Published in: Leukemia research Vol. 17; no. 3; pp. 241 - 245
• Main Authors: Ayyub Khan, M., Tateson, James E., Hoffbrand, A.Victor, Wickremasinghe, R.Gitendra
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.03.1993; Elsevier Science
• Subjects: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine - pharmacology; Antineoplastic agents; Benzeneacetamides; Biological and medical sciences; Blast Crisis; Burkitt Lymphoma - drug therapy; Burkitt Lymphoma - enzymology; Burkitt Lymphoma - pathology; Cell Division - drug effects; Cell Division - physiology; cell proliferation; Epoprostenol - analogs & derivatives; Epoprostenol - pharmacology; General aspects; Hematopoietic System - cytology; Hematopoietic System - metabolism; Hematopoietic System - physiology; Humans; Hydroxamic Acids - pharmacology; Indoles - pharmacology; Leukemia - drug therapy; Leukemia - metabolism; Leukemia - pathology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemia, Promyelocytic, Acute - drug therapy; Leukemia, Promyelocytic, Acute - enzymology; Leukemia, Promyelocytic, Acute - pathology; Leukemia-Lymphoma, Adult T-Cell - drug therapy; Leukemia-Lymphoma, Adult T-Cell - enzymology; Leukemia-Lymphoma, Adult T-Cell - pathology; Leukotriene Antagonists; Leukotrienes; Leukotrienes - biosynthesis; Leukotrienes - physiology; lipoxygenase; Lipoxygenase Inhibitors - pharmacology; Masoprocol - pharmacology; Medical sciences; Pharmacology. Drug treatments; Tumor Cells, Cultured; lipoxygenase; LO, lipoxygenase; cell proliferation; Leukotrienes; ETYA, eicosanetetraeynoic acid; NDGA, nordihydroguiaretic acid; LT, leukotriene; CO, cyclo-oxygenase; Human; Antineoplastic agent; Cell proliferation; Enzyme; Leukemia; Enzyme inhibitor; Malignant hemopathy; In vitro; Leukotriene; Regulation(control); Established cell line; Lipoxygenase; Mechanism of action
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/0145-2126(93)90007-8

The proliferation of malignant hemopoietic cell lines is inhibited by antagonists of 5-lipoxygenase, suggesting that the endogenous generation of leukotrienes via the action of this enzyme may play some role in the proliferation of these cells (Snyder D. S., Castro R. & Desforges J. F. (1989), Expl Hemat. 17, 6). Here we have confirmed that the lipoxygenase inhibitors piriprost, nordihydroguiaretic acid and BW755C decreased DNA synthesis and proliferation of leukemic cell lines. However, the concentrations of these drugs required for half-maximal inhibition of proliferation were significantly greater than their ic 50 values for 5-lipoxygenase inhibition. We therefore studied the actions of two novel, potent lipoxygenase inhibitors, BWA4C and MK886, on proliferation (as measured by estimating the number of viable, trypan blue-excluding cells) and DNA synthesis (measured by the incorporation of radiolabeled thymidine) in the leukemia cell lines HL60, K562 and Jurkat. Neither parameter was affected by concentrations of these drugs which were shown in parallel studies to substantially inhibit leukotriene generation in whole blood. The data show that endogenous leukotriene generation does not play a significant role in the regulation of proliferation of these leukemic cell lines and suggest that conclusions about leukotriene involvement in the control of cellular metabolic pathways based on the use of lipoxygenase inhibitors should be re-assessed.