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We have examined the effects of various inhibitors of the lipoxygenase pathway of arachidonic acid metabolism on the growth of three well-characterized human leukemia cell lines, HL-60, K-562, and KG-1. An intact lipoxygenase pathway, and the synthesis of leukotriene C4 (LTC4), which requires reduced glutathione, is essential for in vitro growth of normal myeioid progenitors (CFU-GM). We tested the effects of nordihydroguiaretic acid (NDGA) and caffeic acid (CA), inhibitors of lipoxygenase; buthionine sulfoximine (BSO), which inhibits glutathione synthesis; and Acivicin, a glutamine antagonist, on these cell lines and compared the effects with those seen on CFU-GM. In semisolid culture, all three cell lines were inhibited by NDGA, CA, and BSO in a dose-dependent manner similar to that in CFU-GM but were relatively resistant to Acivicin. In liquid culture, all three cell lines exhibited relative resistance to inhibition by both BSO and Acivicin, with KG-1 also demonstrating relative resistance to inhibition by NDGA and CA. The inhibition of HL-60 by CA could be completely reversed by the addition of exogenous leukotriene D4. The dependence on the lipoxygenase pathway may be altered to varying degrees in different leukemic lines and may depend on culture conditions. Whether these changes may contribute to the pathogenesis of leukemia or merely represent secondary metabolic changes is yet to be determined.
Abbreviations:BSO (buthionine sulfoximine), CA (caffeic acid), CFU-GM (granulocyte and monocyte progenitor cells), CSF (colony stimulating factor), FBS (fetal bovine serum), LTA4 (leukotriene A4), LTB4 (leukotriene B4), LTC4 (leukotriene C4), LTD4 (leukotriene D4), LTE4 (leukotriene E4), MEM-α (minimum essential medium-α), NDGA (nordihydroguiaretic acid)
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Accepted: November 22, 1988
Received in revised form: September 26, 1988
Received: April 28, 1988
☆Supported by Public Health Service Grant CA 44838 awarded by the National Cancer Institute, Department of Health and Human Services (A.M.M.), and by the Florida Division of the American Cancer Society (M.K.C.).
© 1989 Published by Elsevier Inc.