ABSTRACT
This chapter reviews what is known about the effects of phosphodiesterase (PDE) inhibitors on apoptotic signaling, with an emphasis on the potential role of PDE inhibitors in the treatment of malignancies. In specific cell lineages and under specific circumstances, cyclic nucleotide PDE inhibitors can induce or prevent apoptosis. PDE4 inhibitors have also proven to be efficacious inducers of apoptosis in models of two other lymphoid malignancies, acute lymphoblastic leukemia and diffuse large B-cell lymphoma. The molecular basis for the interrelationship of cAMP and glucocorticoid (GC)-mediated apoptosis in lymphoid cells remains incompletely understood. In addition to the GC receptor literature cited above, other models have been proposed for the mechanism by which PDE4 inhibitors induce apoptosis in lymphoid cells. Cyclic adenosine monophosphate and cyclic guanosine monophosphate signaling induced by PDE inhibitors, hormonal stimuli, forskolin, or cyclic nucleotide analogs inhibits apoptosis in cultured spinal motor, superior cervical ganglion sympathetic, dorsal root sensory, dopaminergic, cerebellar granule, and septal cholinergic neurons.
