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Potential therapeutic applications of phosphodiesterase inhibition in prostate cancer.
MedLine Citation:
PMID:  22383129     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
OBJECTIVE: Phosphodiesterases (PDEs) play a role in controlling cyclic nucleotide action, including cyclic guanosine monophosphate (cGMP). Previous studies have ascribed a protective role of cGMP signaling on hypoxia-mediated cancer progression. Herein, we determine their potential role in hypoxia-mediated chemoresistance and immune escape. MATERIALS AND METHODS: Phosphodiesterase assays were used to measure PDE activity in prostate cancer cell lines (DU145, PC3). Immunoblots were performed to determine the presence of PDEs in human prostate tissue samples. The effect of PDE inhibition on hypoxia-induced chemoresistance (compared to normoxic controls, 20% O(2)) was determined using clonogenic assays. Flow cytometry was used to determine the effects of PDE inhibition on surface MHC class I-related chain A (MICA), a natural killer (NK) cell-activating ligand. A mouse model was used to evaluate the in vivo effects of PDE inhibition on the growth of human prostate cancer cells. RESULTS: PDE5 and PDE11 were the most prominent PDEs in the cell lines, representing between 86 and 95% of the total cGMP-specific PDE activity. Treatment of DU-145 cells with a PDE inhibitor significantly reduced the hypoxia-associated acquisition of resistance to doxorubicin, with a mean 51% reduction in surviving fraction compared to controls (p < 0.001, ANOVA). As well, PDE inhibition completely reversed (p = 0.02, ANOVA) hypoxia-induced shedding of the immune stimulatory molecule, MICA, and attenuated the growth of human prostate tumor xenografts in an NK cell-competent murine model (p = 0.03, Wilcoxon, Mann-Whitney). CONCLUSIONS: These results suggest a rationale for future studies on the potential therapeutic applications of PDE inhibitors in men with prostate cancer.
Authors:
Thomas K Hamilton; Nianping Hu; Klodiana Kolomitro; Erin N Bell; Donald H Maurice; Charles H Graham; D Robert Siemens
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-2
Journal Detail:
Title:  World journal of urology     Volume:  -     ISSN:  1433-8726     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-2     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8307716     Medline TA:  World J Urol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Anatomy and Cell Biology, Queen's University, Kingston, ON, Canada.
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