Purpose: Low tumour oxygenation (hypoxia) correlates with resistance to chemotherapeutic agents. We have recently provided evidence that hypoxia-induced resistance to anti-cancer drugs can be decreased by stimulating nitric oxide (NO) signalling through a cGMP-mediated pathway. An alternative approach to increase the activity of this signalling pathway is to prevent the breakdown of cGMP by phosphodiesterases (PDEs). The aim of this study was to determine whether PDE inhibitors are capable of attenuating hypoxia-induced chemoresistance in prostate carcinoma cells. Materials and Methods: Western blots, immunohistochemistry and functional enzymatic assays were used to determine the expression of PDEs in human cell lines and human prostate cancer samples. Drug sensitivity assays of cell lines exposed to hypoxic or standard conditions were performed in the presence of various concentrations of the PDE-5-specific inhibitor zaprinast. Results: These studies revealed the presence of two of the multiple cGMP-specific PDEs (PDE5 and PDE11A) in both DU145 and PC-3 cell lines and in prostate cancer tissue. Clonogenic assays revealed that incubation of DU145 in 0.5% O2 for 24 hours resulted in a corresponding 4-fold increase (P < 0.001) in their survival following a 1-hour exposure to doxorubicin (12.5 µM). While low concentrations of zaprinast did not affect the sensitivity to doxorubicin in DU145 cells incubated in 20% O2, similar concentrations of this PDE inhibitor inhibited the survival of these cells incubated in 0.5% O2 by up to 50% (P < 0.05). Conclusions: These results describe for the first time the expression of functional cGMP-specific PDEs in prostate cancer and demonstrate a possible role for PDE inhibitors as adjuvants to chemotherapy of prostate cancer patients.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA