Effects of lipoxygenase and glutathione pathway inhibitors on leukemic cell line growth

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 myeloid 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.