PT - JOURNAL ARTICLE AU - Marina Pierdominici AU - Anna Maria Giammarioli AU - Lucrezia Gambardella AU - Marco De Felice AU - Isabella Quinti AU - Metello Iacobini AU - Maurizio Carbonari AU - Walter Malorni AU - Antonello Giovannetti TI - Pyrimethamine (2,4-Diamino-5-<em>p</em>-chlorophenyl-6-ethylpyrimidine) Induces Apoptosis of Freshly Isolated Human T Lymphocytes, Bypassing CD95/Fas Molecule but Involving Its Intrinsic Pathway AID - 10.1124/jpet.105.086736 DP - 2005 Dec 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1046--1057 VI - 315 IP - 3 4099 - http://jpet.aspetjournals.org/content/315/3/1046.short 4100 - http://jpet.aspetjournals.org/content/315/3/1046.full SO - J Pharmacol Exp Ther2005 Dec 01; 315 AB - Pyrimethamine (2,4-diamino-5-p-chlorophenyl-6-ethyl-pyrimidine), a folic acid antagonist, may exert, in addition to antiprotozoan effects, immunomodulating activities, including induction of peripheral blood lymphocyte apoptosis. However, the molecular mechanisms underlying this proapoptotic activity remain to be elucidated. Here we show that pyrimethamine, used at a pharmacologically relevant concentration, induced per se apoptosis of activated lymphocytes via the activation of the caspase-8- and caspase-10-dependent cascade and subsequent mitochondrial depolarization. Importantly, this seems to occur independently from CD95/Fas engagement. The proapoptotic activity of pyrimethamine was further confirmed in a patient with autoimmune lymphoproliferative syndrome, an immune disorder associated with a defect of Fas-induced apoptosis. In this patient, pyrimethamine treatment resulted in a “normalization” of lymphocyte apoptosis with a significant amelioration of laboratory parameters. Altogether, these results suggest a mechanism for pyrimethamine-mediated apoptosis that seems to bypass CD95/Fas engagement but fully overlaps CD95/Fas-induced subcellular pathway. On these bases, a reappraisal of the use of pyrimethamine in immune lymphoproliferative disorders characterized by defects in CD95/Fas-mediated apoptosis should be taken into account. The American Society for Pharmacology and Experimental Therapeutics