Induction of apoptosis by arachidonic acid in chronic myeloid leukemia cells

The hallmark of chronic myeloid leukemia (CML) is the presence of the ber-a bl oncogene, which is associated with transforming ability and an intrinsic resistance to induction of apoptosis by genotype agents. Arachidonic acid (AA), a biologically active fatty acid, plays a crucial role as a mediator of signaling pathways involved in cell proliferation and survival. In this study, we investigated the potential role of AA as a proapoptotic agent in CML. Pretreatment of human CML isolated progenitor cells with AA (100 mu M for 18 h) induced 71-75% inhibition of in vitro colony formation of granulo cyte-macrophage colony-forming units, multilineage colony-forming units, an d erythroid burst-forming units. This inhibition was significantly greater than the effect on normal progenitor cells (19-39% growth inhibition of ery throid burst-forming units, multilineage colony-forming units, and granuloc yte-macrophage colony-forming units). AA also inhibited growth of the bcr-a bl-transformed cell line H7.bcr-abl A54. In contrast, a minimal effect of A A an inhibition of cell growth was observed in the parental nontransformed NSF/N1.H7 cell line, The antiproliferative effect of AA was associated with apoptosis, gamma-Linolenic acid, a precursor of AA, also inhibited cell gr owth, whereas other unsaturated and saturated fatty acids had no effect, ph armacological inhibition of cyclooxygenase, lipooxygenase, and cytochrome P 450 monooxygenase enzymes prior to exposure to AA did not rescue cells from the inhibitory effect of AA, Moreover, 5,8,11,14-eicosatetraynoic acid, a nonmetabolizable arachidonate analogue, also inhibited cell growth, suggest ing that the effect of AA did not require further metabolism. Treatment wit h antioxidants prior to stimulation with AA was also ineffective in prevent ing its antiproliferative effect. Thus, AA inhibited proliferation of CML c ells by inducing apoptotic cell death, The signaling mechanisms of AA-induc ed inhibition of cell growth appeared to be independent of its conversion i nto eicosanoids or free radical generation.