4-hydroxy-2-nonenal and Leukemia--Promyelocytic--Acute

4-Hydroxynonenal is a highly reactive aldehyde, produced by cellular lipid peroxidation, able to inhibit cell proliferation "in vitro" and "in vivo". Its concentration in non proliferating cells ranges up to 1 microM, whereas in the highly undifferentiated tumour cells, it is very low or undetectable. We have now demonstrated that micromolar concentrations of 4-hydroxynonenal inhibit c-myc but not N-ras expression in HL-60 human leukemic cells. This inhibitory effect is observed after an incubation of 1 hour with both 1 and 10 microM aldehyde. Moreover, we report that down-regulation of c-myc expression increases when repeated additions of 1 microM 4-hydroxynonenal are performed, to maintain the cells in presence of aldehyde for 7.5 hours. These results indicate that not only the concentration but also the length of exposure to the aldehyde is important in determining the extent of the c-myc expression inhibition and suggest a role of lipid peroxidation products in the control of gene expression.

Topics: Aldehydes; Cell Division; Cell Line; Gene Expression; Genes, myc; Genes, ras; Humans; Kinetics; Leukemia, Promyelocytic, Acute; Lipid Peroxidation; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins p21(ras); Time Factors; Tumor Cells, Cultured

4-Hydroxynonenal (HNE), a major lipid peroxidation product, displays several biological actions. Among them, the differentiation of human HL-60 cells and the stimulation of neutrophil oriented migration occur at concentrations which can be actually found in normal tissues and in body fluids. In spite of its chemotactic activity, HNE fails to increase neutrophil oxidative metabolism. The action of the aldehyde on cell migration appears to be mediated by a phosphoinositide specific phospholipase C. The acceleration of phosphatidylinositol turnover induced by 10 pM 4-hydroxyoctenal, another lipid peroxidation product, is prevented by the pretreatment of neutrophils with pertussis toxin. The mechanism of action of these 4-hydroxyalkenals appears to follow pathways common to other chemoattractants, but some differences can be found too. In particular HNE seems unable to stimulate phospholipase D activity. The action of 4-hydroxyalkenals and other lipid peroxidation products on transmembrane signalling systems and on phospholipid metabolism might regulate several cell functions, such as motility, proliferation and differentiation.

Topics: Aldehydes; Animals; Guanosine Triphosphate; Humans; Kinetics; Leukemia, Promyelocytic, Acute; Lipid Peroxidation; Male; Neutrophils; Phosphatidylinositol Diacylglycerol-Lyase; Phosphoric Diester Hydrolases; Rats; Rats, Wistar; Tumor Cells, Cultured

4-Hydroxynonenal (HNE) is the major diffusible toxic product generated by lipid peroxidation of cellular membranes. The level of lipid peroxidation and, consequently, the concentration of its products are inversely related to the rate of cell proliferation and directly related to the level of cell differentiation. In the present paper the effects of HNE on the proliferation and differentiation of the HL-60 human promyelocytic cell line have been investigated. Repeated treatment at 45-min intervals with HNE (1 microM) was performed to maintain the cells in the presence of the aldehyde for 7 1/2 or 9 h. The effect of HNE on cell proliferation and differentiation was compared with dimethyl sulfoxide (DMSO)-treated cells. HNE causes a strong inhibition of cell growth without affecting cell viability. Moreover, HL-60 cells acquire the capability to produce chemiluminescence after soluble (phorbol myristate acetate) or corpuscolate (zymosan) stimulation. The phagocytic ability has also been calculated by counting the number of cells that phagocytize opsonized zymosan. Values were 43 and 55% after 10 or 12 HNE treatments, respectively, and 88% in DMSO-treated cells. Myeloperoxidase activity, 5 days after treatment, decreased by 85% in either HNE- or DMSO-treated cells while acid phosphatase activity increased with respect to untreated cells. Results obtained indicate that HNE at concentrations close to those found in the normal tissues can induce inhibition of proliferation and induction of differentiation in the HL-60 cell line.

Topics: Aldehydes; Alkaline Phosphatase; Cell Differentiation; Cell Line; Dimethyl Sulfoxide; DNA Replication; Humans; Kinetics; Leukemia, Promyelocytic, Acute; Lipid Peroxidation; Luminescent Measurements; Thymidine