Induction of neutrophilic differentiation of human promyelocytic leukemic cells by branched-chain carboxylic acid anticonvulsant drugs.

The anticonvulsant drug 1-methyl-1-cyclohexanecarboxylic acid ( MCCA ) has been shown to cause maturation of murine neuroblastoma cells in vitro at concentrations that are pharmacologically achievable. HL-60 human promyelocytic leukemia cells cultured with this drug underwent a dose-dependent decrease in growth. Similarly, neutrophilic differentiation, based on morphologic criteria and the acquisition of the ability to reduce nitroblue tetrazolium and phagocytose yeast, was observed. Valproic acid, a clinically available anticonvulsant that is chemically related to MCCA , likewise inhibited growth and promoted maturation of HL-60 cells, although only at concentrations above the recommended therapeutic blood levels. MCCA was additive in its ability to induce differentiation of HL-60 with retinoic acid, another compound that induces differentiation at pharmacologic concentrations. MCCA , or similar branched-chain fatty acids, may be useful in the treatment of human leukemia, particularly in combination with other differentiation-inducing drugs.