6-Mercaptopurine decreases the Bcl-2/Bax ratio and induces apoptosis in activated splenic B lymphocytes.
6-Mercaptopurine and related purine antimetabolites are used in the treatment of several B cell disorders. These drugs inhibited the proliferation of mature splenic B cells after being triggered with polyclonal mitogens. In addition to the antiproliferative effects, 6-mercaptopurine, 2-mercaptopurine, and aminoguanidine evoked a rapid apoptotic cell death in activated B cells that started at 6 hr after drug treatment and therefore preceded DNA synthesis. Incubation of activated B lymphocytes with 6-mercaptopurine blocked the low but sustained nitric oxide release observed in these cells that contributes to the prevention of apoptotic cell death; the addition of chemical nitric oxide donors significantly antagonized the apoptosis elicited by these drugs. The inhibition of nitric oxide synthesis elicited by mercaptopurines correlated with a decrease in the release of nitric oxide-derived species to the culture medium and in the intracellular levels of cGMP. The ratio between the amounts of Bcl-2 and Bax, two proteins involved in the control of apoptosis in mature B cells, markedly decreased as result of mercaptopurine treatment.
Hortelano
S
S
Instituto de Bioquimica (Centro Mixto CSIC-UCM), Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
Boscá
L
L
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000187:drug effects*; D008213:Lymphocyte Activation; D015122:Mercaptopurine / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D009569:Nitric Oxide; D015122:Mercaptopurine