PT - JOURNAL ARTICLE AU - Min Huang AU - Yanhong Wang AU - Matthew Collins AU - Beverly S. Mitchell AU - Lee M. Graves TI - A77 1726 Induces Differentiation of Human Myeloid Leukemia K562 Cells by Depletion of Intracellular CTP Pools AID - 10.1124/mol.62.3.463 DP - 2002 Sep 01 TA - Molecular Pharmacology PG - 463--472 VI - 62 IP - 3 4099 - http://molpharm.aspetjournals.org/content/62/3/463.short 4100 - http://molpharm.aspetjournals.org/content/62/3/463.full SO - Mol Pharmacol2002 Sep 01; 62 AB - A77 1726 (LEF) is the active metabolite of leflunomide, a recently approved immunosuppressive agent. We examined the ability of LEF to induce differentiation of a human erythroleukemia (K562) cell line and show that LEF induces a dose- and time-dependent differentiation of these cells as characterized by growth inhibition, hemoglobin production, and erythroid membrane protein glycophorin A expression. This effect was dependent on depletion of the intracellular pyrimidine ribonucleotides (UTP and CTP), and preceded by a specific S-phase arrest of the cell cycle. Supplementation of the cultures with exogenous uridine restored intracellular UTP and CTP to normal levels and prevented the LEF-induced cell cycle block and differentiation of K562 cells. Interestingly, addition of cytidine alone blocked the LEF-induced differentiation of K562 cells but only restored the CTP pool. By contrast, neither deoxycytidine nor thymidine prevented the effects of LEF on these cells. Similarly, pyrimidine starvation of a cell line lacking the de novo pyrimidine pathway (G9c) resulted in an S-phase arrest that was reversed by the addition of cytidine. Thus these studies demonstrate an important role for CTP in regulating cell cycle progression and show that LEF is an effective inducer of tumor cell differentiation through depletion of this ribonucleotide.