Theophylline-induced B-CLL apoptosis is partly dependent on cyclic AMP production but independent of CD38 expression and endogenous IL-10 production.
Our recent work has shown that theophylline which inhibits intracellular cyclic adenosine monophosphate (cAMP) degradation is able to kill chronic lymphocytic leukemia (CLL) cells in vitro and synergizes in vitro and in vivo with chlorambucil. In order to test the hypothesis that theophylline works through an indirect increase in cAMP, we have investigated the role of several molecules on B-CLL cells from 20 patients. Direct cAMP inducers such as dibutyryl-cAMP (db-cAMP), prostaglandin-E2 (PGE2) and forskolin induced moderate apoptosis but extremely high levels of intracellular cAMP. By contrast theophylline was highly apoptotic but did not synergize with cAMP inducers. Apoptosis was completely reversed by a cAMP antagonist when induced by PGE2 or forskolin, but was only partially antagonized when induced by theophylline. Since CD38+ CLL cells are more sensitive to apoptosis and since CD38 is enhanced by cAMP inducing agents its expression was investigated. In our hands CD38 was not induced by the above pharmacological compounds. Exogenous IL-10 has been shown to induce CLL cell death; however, apoptosis following treatment with theophylline or cAMP inducers could not be ascribed to endogenous production of IL-10. This ruled out the involvement of cytokines or of an activation or differentiation process in apoptosis. Altogether our data show that an increase in intracellular cAMP mediates apoptosis in vitro but accounts only partly for theophylline-mediated apoptosis.
Laboratoire d'Hematologie, UMR 7627, Hopital Pitié-Salpêtrière, Paris, France.
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Mentz
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Merle-Beral
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Dalloul
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD / Q000096:biosynthesis; D000943:Antigens, Differentiation / Q000096:biosynthesis*; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000096:biosynthesis*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood* / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins; D009244:NAD+ Nucleosidase / Q000096:biosynthesis*; D013806:Theophylline / Q000494:pharmacology*; D013873:Thionucleotides / Q000494:pharmacology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; D013873:Thionucleotides; D016753:Interleukin-10; D005576:Colforsin; C016957:adenosine-3',5'-cyclic phosphorothioate; D003994:Bucladesine; D013806:Theophylline; D000242:Cyclic AMP; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D015232:Dinoprostone