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)

Deuterium oxide (D2O), which is known to stimulate microtubule aggregation, enhanced the IgE-mediated 45Ca2+ influx, (14C)-arachidonic acid and histamine release in rat basophilic leukemia cells (RBL-2H3) in the same dose-dependent manner (up to 90% (v/v]. We compared the interaction between D2O and a variety of groups of pharmacological agents. A microtubule depolymerizing agent, demecolcine, which inhibited the IgE-mediated (14C)-arachidonic acid and histamine release without affecting 45Ca2+ influx, was counteracted by 45% D2O. Taxol, a microtubule stabilizing agent, which had an inhibitory effect on the above three steps, was also reversed by 45% D2O. These results would support the previous data on the interaction between D2O and microtubules and would further suggest that the status of microtubule aggregation may be related to the secretory process. Calmodulin inhibitors (W-7, trifluoperazine) blocked the IgE-mediated 45Ca2+ influx, (14C)-arachidonic acid and histamine release in the same dose-dependent manner, but were counteracted by 45% D2O. In contrast, the effects of proteinase inhibitors (TPCK, TLCK), an adenylate cyclase inhibitor (ddAdo), a phosphodiesterase inhibitor (aminophylline), a phospholipid methylation inhibitor (DZA + Hcy) and microfilament blockers (cytochalasin B and D) were not counteracted by 45% D2O. These results would suggest that D2O may be associated with calmodulin directly or indirectly possibly through some relationship between calmodulin and microtubules.
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PMID:Effect of deuterium oxide (D2O) on the IgE-mediated Ca2+ influx, arachidonic acid and histamine release in rat basophilic leukemia cells. 247 27

We have found that the synthetic compound CC-5079 potently inhibits cancer cell growth in vitro and in vivo by a novel combination of molecular mechanisms. CC-5079 inhibits proliferation of cancer cell lines from various organs and tissues at nanomolar concentrations. Its IC(50) value ranges from 4.1 to 50 nmol/L. The effect of CC-5079 on cell growth is associated with cell cycle arrest in G(2)-M phase, increased phosphorylation of G(2)-M checkpoint proteins, and apoptosis. CC-5079 prevents polymerization of purified tubulin in a concentration-dependent manner in vitro and depolymerizes microtubules in cultured cancer cells. In competitive binding assays, CC-5079 competes with [(3)H]colchicine for binding to tubulin; however, it does not compete with [(3)H]paclitaxel (Taxol) or [(3)H]vinblastine. Our data indicate that CC-5079 inhibits cancer cell growth with a mechanism of action similar to that of other tubulin inhibitors. However, CC-5079 remains active against multidrug-resistant cancer cells unlike other tubulin-interacting drugs, such as Taxol and colchicine. Interestingly, CC-5079 also inhibits tumor necrosis factor-alpha (TNF-alpha) secretion from lipopolysaccharide-stimulated human peripheral blood mononuclear cells (IC(50), 270 nmol/L). This inhibitory effect on TNF-alpha production is related to its inhibition of phosphodiesterase type 4 enzymatic activity. Moreover, in a mouse xenograft model using HCT-116 human colorectal tumor cells, CC-5079 significantly inhibits tumor growth in vivo. In conclusion, our data indicate that CC-5079 represents a new chemotype with novel mechanisms of action and that it has the potential to be developed for neoplastic and inflammatory disease therapy.
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PMID:The synthetic compound CC-5079 is a potent inhibitor of tubulin polymerization and tumor necrosis factor-alpha production with antitumor activity. 1642 30

Controlling neuropathic pain is an unmet medical need and we set out to identify new therapeutic candidates. AV411 (ibudilast) is a relatively nonselective phosphodiesterase inhibitor that also suppresses glial-cell activation and can partition into the CNS. Recent data strongly implicate activated glial cells in the spinal cord in the development and maintenance of neuropathic pain. We hypothesized that AV411 might be effective in the treatment of neuropathic pain and, hence, tested whether it attenuates the mechanical allodynia induced in rats by chronic constriction injury (CCI) of the sciatic nerve, spinal nerve ligation (SNL) and the chemotherapeutic paclitaxel (Taxol). Twice-daily systemic administration of AV411 for multiple days resulted in a sustained attenuation of CCI-induced allodynia. Reversal of allodynia was of similar magnitude to that observed with gabapentin and enhanced efficacy was observed in combination. We further show that multi-day AV411 reduces SNL-induced allodynia, and reverses and prevents paclitaxel-induced allodynia. Also, AV411 cotreatment attenuates tolerance to morphine in nerve-injured rats. Safety pharmacology, pharmacokinetic and initial mechanistic analyses were also performed. Overall, the results indicate that AV411 is effective in diverse models of neuropathic pain and support further exploration of its potential as a therapeutic agent for the treatment of neuropathic pain.
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PMID:The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain. 1817 32