Phosphodiesterase 7 (PDE7) and PDE4/7 inhibitors kill chronic lymphocytic leukemia (CLL) cells via a cAMP‐mitochondrial‐dependent pathway

Abstract

Chronic lymphocytic leukemia (CLL), the major form of adult leukemia, is characterized by accumulation of B‐cells. We have found drugs that raise cAMP can kill malignant lymphocytes and (compared to normal peripheral blood mononuclear cells (PBMC) and normal B‐cells) CLL cells overexpress PDE7B, which selectively catalyzes the hydrolysis of cAMP. Furthermore, we found that CLL cells are more sensitive to PDE7 and PDE4/7 inhibitor‐induced apoptosis compared to normal B‐cells. Using CLL cells we sought to investigate the mechanism of PDE7 and PDE4/7‐induced apoptosis. Inhibition of PDE7 (30 μ]M BRL‐50481, 10 μM IR‐202) and dual inhibition of PDE4 and PDE7 (100 nM IR‐284) increased basal and forskolin‐stimulated cAMP accumulation in CLL cells, suggesting that their pro‐apoptotic effect occurs via a cAMP‐dependent mechanism. BRL‐50481, IR‐202 and IR‐284 all induced mitochondrial depolarization, assessed using a MitoProbe JC‐1 assay kit, (13 ± 4 %; 17 ± 6 %; 39 ± 5 % depolarization, respectively vs. vehicle) and cytochrome c release from the mitochondria into the cytosol, visualized by immunofluoresence. We conclude that PDE inhibitor‐induced apoptosis of CLL cells occurs via a cAMP‐mitochondrial‐dependent mechanism and that PDE7 inhibition may be a novel therapeutic approach in CLL. Supported by the Lymphoma and Leukemia Society, NIH and Swiss Cancer League.