Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue destruction, resulting in emphysema, can be a consequence of several pathologic processes. The current study evaluated the effects of the phosphodiesterase (PDE)4 inhibitor, cilomilast, and other PDE inhibitors on the ability of fibroblasts to degrade extracellular matrix. Using the three-dimensional collagen gel culture system, fibroblasts (HFL-1) were cultured with tumor necrosis factor (TNF)-alpha, known to induce matrix metalloproteinase (MMP) release, and/or neutrophil elastase (NE), which can induce MMP activation. On Day 4, gels containing TNF-alpha and NE were significantly degraded (20.8 +/- 2.9% of original collagen content). Cilomilast (10 micro M) inhibited this degradation (84.4 +/- 8.4%). Amrinone, a PDE3 inhibitor, and zaprinast, a PDE5 inhibitor, had no effect. Gelatin zymography and immunoblotting revealed that fibroblasts cultured with TNF-alpha released increased amounts of latent MMP-1 and -9. The addition of NE resulted in the conversion of MMP-1 and -9 to their active forms, indicative of collagen degradation. Cilomilast inhibited the release of MMP-1 and -9, as well as conversion of MMP-1 to its active form. Using real-time PCR analysis, cilomilast's effect on MMP-1 release was not associated with the proteinase's mRNA expression, suggesting that the inhibition of release is regulated at the post-transcriptional level. These results suggest that cilomilast may be a potentially effective therapeutic agent in diseases characterized by excessive tissue destruction, such as emphysema.
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PMID:Phosphodiesterase 4 inhibitor cilomilast inhibits fibroblast-mediated collagen gel degradation induced by tumor necrosis factor-alpha and neutrophil elastase. 1235 83

Melanoma is the most common malignant skin cancer, appears indestructible and is notoriously resistant to all current modalities of cancer treatment strategies. Pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor, has shown to have radiosensitizing properties for a variety of cancers. Recently, we have shown that PTX exhibits antimetastatic and anti-angiogenic activities in B16F10 melanoma cells in vitro as well as in vivo. In the present study, we have demonstrated the anticancer and antimetastatic potential of PTX against A375 human melanoma cell line at sub-toxic doses. The results implicate that PTX at sub-toxic doses exhibited an inhibitory effect on the ability of cellular proliferation as shown by MTT and colony formation assay. It impedes migration and also induces apoptosis. A375 cells pretreated with PTX showed decrease in adhesion to both Matrigel and Collagen type IV. Further, Gelatin zymography result reveals that PTX treatment decreases the secretion of MMP2 and MMP9. Finally, PTX significantly inhibited A375 subcutaneous tumour xenograft growth without having any toxicity. Thus PTX at sub-toxic doses affected melanoma metastasis at multiple steps in vitro as well as tumour growth in vivo. These data demonstrate its antimetastatic potential and provide preclinical evidence for the development of PTX as a potential agent against metastatic melanoma.
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PMID:Preclinical evaluation of the antimetastatic efficacy of Pentoxifylline on A375 human melanoma cell line. 2308 70