Goettingen, Germany, October 02, 2014 --(PR.com
)-- In a paper published in 2009, researchers led by Paul Marker at UW-Madison, identified Phosphodiesterase 4D (PDE4D) as a novel proliferation-promoting factor in prostate cancer. Now, the same researchers have examined the effects of two selective PDE4D inhibitors, NVP-ABE171 and cilomilast, as anti-prostate cancer therapies in both in vitro and in vivo models.
Their results, published last month in Molecular Cancer Research (URL: http://www.ncbi.nlm.nih.gov/pubmed/?term=Phosphodiesterase+4D+Inhibitors+Limit+Prostate+Cancer+Growth+Potential), suggest that silencing PDE4D using small molecule inhibitors may be an effective option for prostate cancer therapy. The team went on to show that the mechanism of PDE inhibition involved stromal-epithelial signaling via the Sonic Hedgehog (SHH) pathway. To examine paracrine signaling they used a microchannel device developed by our long-time collaborator and friend, Dave Beebe , also at UW-Madison, that relies on the passive pumping technology used in BellBrook’s iuvo® Microchannel plates (URL: http://www.bellbrooklabs.com/products-services/iuvo-microconduit-array-platform).
In previous studies, the researchers had showed that stable knockdown of PDE4D in cell lines reduced the growth of prostate cancer epithelial cells. These results, coupled with the published literature demonstrating in vivo efficacy of PDE4D inhibitors in lung, melanoma, and gastric cancer, led the researchers to hypothesize that inhibiting PDE4D would be effective for prostate cancer as well. The researchers used two second-generation PDE4D inhibitors, NVP-ABE171 and cilomilast, which were chosen for their high selectivity and limited side effects observed in previous studies in animal models.
The researchers hypothesized that PDE4 has a stimulatory effect on pancreatic cancer: by hydrolyzing cAMP, PDE4 decreases protein kinase A (PKA) activity, which in turn decreases down-regulation of the SHH pathway, resulting in stimulation of prostate cancer. They first showed that cilomilast and NVP-ABE171 caused dose dependent decreases in prostate cancer cell (LNCaP-C4) proliferation, and, consistent with their hypothesis, the inhibitors down-regulated expression of genes regulated by SHH. This is where things got interesting, because previous reports had indicated that LNCaP cells lack autocrine SHH signaling capacity.
In order to further explore the connection between PDE4D and the SHH pathway, the researchers used a microchannel device in which mesenchymal and LnCaP cells were physically separated and able to communicate solely via paracrine signaling. With this model for stromal-epithelial signaling, they demonstrated that a) activation of the SHH pathway in the mesenchymal cells stimulated LnCap-C4 cell proliferation and b) treatment with the PDE inhibitors eliminated the SHH-dependent LnCap-C4 cell proliferation. Their results suggest that PDE4D may be affecting prostate cancer growth by modulating SHH paracrine signaling between the stroma and epithelium.
The researchers next measured the effects of PDE4D inhibition in mice, using a prostate cancer xenograft model and found that cilomilast and NVP-ABE171 treatment decreased tumor weight 85% and 70%, respectively. Collectively, the complimentary results from in vivo and in vitro studies suggest that PDE4D inhibitors may be efficacious as an anti-prostate cancer therapy. In addition, the researchers hope their results can act as a launching pad for future research exploring the therapeutic efficacy of using PDE4D inhibitors in combination with hedgehog inhibitors. The use of the microchannel-based paracrine signaling assay highlights the importance of thinking “outside the well” for elucidating and targeting tumorigenic pathways.
Learn How to Profile Phosphodiesterases Using the AMP/GMP TR-FRET Assay:
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