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Nonsteroidal antiinflammatory drugs (NSAIDs), have cancer preventive and tumor regressive effects in the human colon. They lower the incidence of and mortality from colorectal cancer and sulindac reduces the number and size of polyps in patients with familial adenomatous polyposis. We studied the effect of sulindac, and its metabolite sulindac sulfide, on(More)
Nonsteroidal anti-inflammatory drugs lower the incidence of and mortality from colon cancer. Sulindac reduces the number and size of polyps in patients with familial adenomatous polyposis. We have shown that sulindac and sulindac sulfide reversibly reduce the proliferation rate of HT-29 colon cancer cells, alter their morphology, induce them to accumulate(More)
Phosphodiesterase (PDE) 8A and PDE8B are high-affinity, cAMP-specific phosphodiesterases that are highly expressed in Leydig cells. PDE8A is largely associated with mitochondria, whereas PDE8B is broadly distributed in the cytosol. We used a new, PDE8-selective inhibitor, PF-04957325, and genetically ablated PDE8A(-/-), PDE8B(-/-) and PDE8A(-/-)/B(-/-) mice(More)
The kynurenine pathway of tryptophan degradation is hypothesized to play an important role in Huntington disease, a neurodegenerative disorder caused by a polyglutamine expansion in the protein huntingtin. Neurotoxic metabolites of the kynurenine pathway, generated in microglia and macrophages, are present at increased levels in the brains of patients and(More)
Staurosporine (ST), a potent inhibitor of protein kinase C (PKC), was evaluated for its effect on the proliferation of HT-29 colon adenocarcinoma cells; PKC is associated with increased colon cell proliferation. ST inhibited cell proliferation in a time- and concentration-dependent manner by up to 90%. It also blocked the G2/M phase of the cell cycle and(More)
The functions of the phosphodiesterase 8B (PDE8) family of phosphodiesterases have been largely unexplored because of the unavailability of selective pharmacological inhibitors. Here, we report a novel function of PDE8B as a major regulator of adrenal steroidogenesis using a genetically ablated PDE8B mouse model as well as cell lines treated with either a(More)
Atypical protein kinase C (aPKC) enzymes signal on protein scaffolds, yet how they are maintained in an active conformation on scaffolds is unclear. A myristoylated peptide based on the autoinhibitory pseudosubstrate fragment of the atypical PKCζ, zeta inhibitory peptide (ZIP), has been extensively used to inhibit aPKC activity; however, we have previously(More)
The functions of the PDE8 family of phosphodiesterases have been largely unexplored due to the unavailability of selective pharmacological inhibitors. Here we report a novel function of PDE8B as a major regulator of adrenal steroidogenesis using a genetically ablated PDE8B mouse model as well as cell lines treated with either a new PDE8-selective inhibitor(More)
The second messenger, cAMP, is one of the most important regulatory signals for control of steroidogenesis. This review focuses on current knowledge about regulation of cyclic nucleotides by phosphodiesterases (PDEs) in steroidogenic tissues. The first PDE known to directly regulate steroidogenesis was PDE2, the cGMP-stimulated PDE. PDE2 mediates(More)
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