Phosphodiesterase type 4 inhibitor suppresses expression of anti-apoptoticmembers of the Bcl-2 family in B-CLL cells and induces caspase-dependent apoptosis

B cell chronic lymphocytic leukemia (B-CLL) is an incurable clonal disease which shows initial responsiveness to a number of chemotherapeutic drugs. H owever, in most patients the disease becomes resistant to treatment. Rolipr am, a specific inhibitor of phosphodiesterase (PDE) type 4, the PDE predomi nantly expressed in B-CLL cells, has been shown to induce cAMP-dependent ap optosis in these cells. In the present study, we demonstrate that the exten t of rolipram-induced apoptosis is similar to fludarabine-induced apoptosis in vitro. The combination of rolipram and fludarabine results in an enhanc ement in the number of apoptotic cells compared to apoptosis induced by eit her agent alone. Second, rolipram suppresses the expression of anti-apoptot ic members of the Bcl-2 family and induces the pro-apoptotic protein Bax, t hereby shifting the balance between pro- and anti-apoptotic members of the Bcl-2 family towards a pro-apoptotic direction. Finally rolipram-induced ap optosis is caspase-dependent. PDE 4 inhibitors are currently under investig ation for chronic obstructive pulmonary disease and asthma in phase III cli nical trials showing promising results with tolerable side-effects. In conc lusion, by inducing apoptosis, by enhancing apoptosis induced by fludarabin e, by suppressing Bcl-2, Bcl-X and by inducing Bax expression, PDE 4 inhibi tors may add a new therapeutic option for patients with B-CLL.