QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.086736v1 315/3/1046    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pierdominici, M. Articles by Giovannetti, A. Search for Related Content PubMed PubMed Citation Articles by Pierdominici, M. Articles by Giovannetti, A.

CELLULAR AND MOLECULAR

Pyrimethamine (2,4-Diamino-5-p-chlorophenyl-6-ethylpyrimidine) Induces Apoptosis of Freshly Isolated Human T Lymphocytes, Bypassing CD95/Fas Molecule but Involving Its Intrinsic Pathway

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy (M.P., M.D.F.); Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy (A.M.G., L.G., W.M.); and Department of Clinical Medicine, Division of Clinical Immunology (I.Q., M.C., A.G.), and Department of Pediatrics, University of Rome "La Sapienza", Rome, Italy (M.I.)

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.

Address correspondence to: Dr. Walter Malorni, Section of Cell Aging and Degeneration, Department of Drug Research and Evaluation, Viale Regina Elena 299, 00161 Rome, Italy. E-mail: malorni{at}iss.It

This article has been cited by other articles:

				A. M. Giammarioli, A. Maselli, A. Casagrande, L. Gambardella, A. Gallina, M. Spada, A. Giovannetti, E. Proietti, W. Malorni, and M. Pierdominici Pyrimethamine Induces Apoptosis of Melanoma Cells via a Caspase and Cathepsin Double-Edged Mechanism Cancer Res., July 1, 2008; 68(13): 5291 - 5300. [Abstract] [Full Text] [PDF]