The Role of Prostaglandins and Other Arachidonic Acid Metabolites in the Differentiation of HL-60
Recently, there has been interest in the possibility that “differentiation inducers” may have utility in the treatment of some malignancies. This concept is predicated on the belief that some malignancies are a result of a block in differentiation which if relieved would result in a more differentiated and therefore more benign malignancy. As a concept for therapy this approach holds the further promise that induction of differentiation could not only relieve the tumor burden but also increase the number of functional cells, the absence of which at least for some malignancies, is a major complication. HL-60 has been a useful model system in the search for substances that are active as inducers of differentiation. HL-60 is induced to differentiate to granulocyte-like cells by incubation with retinoic acid (RA), N,N-dimethylformamide, and dimethyl sulfoxide or into monocyte/macrophage-like cells by incubation with l,25-dihydroxyvitamin D3, butyrate, and 12-O-tetradecanoyl phorbol-13-acetate (TPA). Of the many compounds that induce differentiation of HL-60, RA has probably the most promise of being of use in the clinic. This is because it is active at physiological concentrations in vitro; has been shown to induce differentiation of fresh human leukemia cells in primary culture; and has been reported to be effective on patients with some leukemias. To the extent that it is possible, results in vitro should suggest treatments in vivo. To this end we have been interested in determining which induction conditions result in the most “normal” mature HL-60. The studies to be presented indicate that combinations of RA and PGE2 synergistically induce the differentiation of HL-60 and that differentiated HL-60 cells are functional in producing cyclooxygenase and lipoxygenase products from arachidonic acid.
KeywordsDMSO Leukemia Cortisol Aspirin Dexamethasone
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