Interaction of Antileukemia Agents Adriamycin and Daunomycin with Sphinganine on the Differentiation of Human Leukemia Cell Line HL-60

A slight induction of granulocytic differentiation of HL-60 cells occurred after treatment with antileukemia chemotherapeutic agents Adriamycin (ADM) and daunomycin (DM). Addition of an inhibitor (sphinganine, SP) of protein kinase C (PKC) enhanced 2-4-fold the ADM or DM-induced differentiation. This phenomenon was accompanied by a slightly augmented antiproliferative effect. The enhancement of differentiation induction in these treatments seemed to be absolute, since the combination treatment (ADM-SP or DM-SP) showed about 2.5-3.6 times as many differentiated cells as the treatment with the anticancer drugs ADM or DM alone. Further characterization of the interaction of ADM and DM with SP on differentiation of HL-60 cells was carried out. Whereas the addition of SP in the fresh medium after the removal of ADM or DM (0.5 h treatment) enhanced the induction of differentiation, a pretreatment (24 h) of the cells with SP followed by continuous exposure to ADM or DM did not show such enhancement effect. The addition of SP at as late as 48 h after the administration of ADM or DM potentiated the induction of differentiation to the same extent as in the simultaneous combination of ADM-SP or DM-SP. Similar results were obtained in the experiments with another PKC inhibitor, staurosporine. These results indicated that inhibition of PKC activities may play an important role in the later events during the induction of differentiation elicited by ADM or DM. The use of the antileukemia drugs ADM and DM in combination with an inhibition of PKC activity results in enhancement of induction of differentiation and suggests a new strategy and a promising approach to the treatment of leukemia.