Biochemical pharmacology
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Biochemical pharmacology · Apr 2009
ReviewLiver X receptor modulators: effects on lipid metabolism and potential use in the treatment of atherosclerosis.
Liver X receptors (LXRs) are nuclear receptors that play a crucial role in regulating the expression of genes involved in lipid metabolism. Ligand activation of LXRs improves cholesterol homeostasis via multiple coordinated effects, and this function is likely to explain in part the protective effects of LXR activation on atherosclerosis reported in animal models. However, LXR activation may also induce undesirable side effects, such as lipogenesis and hypertriglyceridemia. This review discusses the potential to develop LXR modulators as therapeutic agents for atherosclerosis.
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Biochemical pharmacology · Mar 2009
Comparative StudyAspirin and indomethacin reduce lung inflammation of mice exposed to cigarette smoke.
Neutrophil accumulation response to cigarette smoke (CS) in humans and animal models is believed to play an important role in pathogenesis of many tobacco-related lung diseases. Here we evaluated the lung anti-inflammatory effect of aspirin and indomethacin in mice exposed to CS. C57BL/6 mice were exposed to four cigarettes per day during 4 days and were treated i.p. with aspirin or indomethacin, administered each day 1h before CS exposure. ⋯ Aspirin or indomethacin treatment led to a significant reduction of neutrophil influx, but only aspirin resulted in dramatic decrease of inflammatory mediators. Moreover, both drugs reduced lung p38 MAPK and NF-kappaB activation induced by CS. These results demonstrate that short-term CS exposure has profound airway inflammatory effects counteracted by the anti-inflammatory agents aspirin and indomethacin, probably through COX-dependent and -independent mechanisms.
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Biochemical pharmacology · Feb 2009
The novel pyrrolo-1,5-benzoxazepine, PBOX-21, potentiates the apoptotic efficacy of STI571 (imatinib mesylate) in human chronic myeloid leukaemia cells.
The Bcr-Abl kinase inhibitor, STI571, is the first line treatment for chronic myeloid leukaemia (CML), but the recent emergence of STI571 resistance has led to the examination of combination therapies. In this report, we describe how a novel non-toxic G1-arresting compound, pyrrolo-1,5-benzoxazepine (PBOX)-21, potentiates the apoptotic ability of STI571 in Bcr-Abl-positive CML cells. Co-treatment of CML cells with PBOX-21 and STI571 induced more apoptosis than either drug alone in parental (K562S and LAMA84) and STI571-resistant cells lines (K562R). ⋯ Apoptosis was significantly reduced following pre-treatment with either the general caspase inhibitor Boc-FMK or the chymotrypsin-like serine protease inhibitor TPCK, but was completely abrogated following pre-treatment with a combination of these inhibitors. This demonstrates the important role for each of these protease families in this apoptotic pathway. In conclusion, our data highlights the potential of PBOX-21 in combination with STI571 as an effective therapy against CML.
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Biochemical pharmacology · Dec 2008
Kinetic stabilization of microtubule dynamic instability by benomyl increases the nuclear transport of p53.
Using time-lapse confocal microscopy and enhanced green fluorescent protein-tubulin transfected MCF-7 cells, we found that a tubulin-targeted antimitotic agent, benomyl at its half-maximal proliferation inhibitory concentration (5 microM) strongly suppressed the rate and extent of growing and shortening excursions of individual microtubules in MCF-7 cells without noticeably depolymerizing the microtubule network or decreasing the polymerized mass of tubulin. Further, benomyl treatment caused an increase in the acetylation level of microtubules suggesting that it stabilizes microtubules. Under the conditions that suppressed the dynamic instability, a sharp increase in the nuclear accumulation of p53 in MCF-7 cells was observed in the presence of benomyl. ⋯ Cisplatin caused an increase in the translocation of p53 into the nucleus in the presence of lower effective concentrations of benomyl while a decrease in the nuclear accumulation of p53 was observed in the presence of high concentrations of benomyl suggesting that the stabilized microtubules assist in the nuclear transportation of p53. Furthermore, increased localization of the light chain of the minus end directed motor protein dynein was detected on the microtubules in the benomyl-treated cells indicating that the suppression of microtubule dynamics may influence the binding of dynein on the microtubules and dynein-mediated cargo transport. Together the data indicate that benomyl inhibits mitosis primarily by suppressing the dynamic instability of microtubules and support the hypothesis that the kinetic stabilization of microtubules enhances the microtubule-mediated transport of p53 into the nucleus.
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Biochemical pharmacology · Jul 2008
The anti-proliferative potency of celecoxib is not a class effect of coxibs.
Celecoxib, a COX-2 (cyclooxygenase-2)-selective inhibitor (coxib), is the only NSAID (non-steroidal anti-inflammatory drug) that has been approved for adjuvant treatment of patients with familial adenomatous polyposis. To investigate if the anti-proliferative effect of celecoxib extends to other coxibs, we compared the anti-proliferative potency of all coxibs currently available (celecoxib, rofecoxib, etoricoxib, valdecoxib, lumiracoxib). Additionally, we used methylcelecoxib (DMC), a close structural analogue of celecoxib lacking COX-2-inhibitory activity. ⋯ Among all coxibs tested, only celecoxib and methylcelecoxib decreased cell survival by induction of cell cycle arrest and apoptosis and reduced the growth of tumor xenografts in nude mice. None of the other coxibs (rofecoxib, etoricoxib, valdecoxib, lumiracoxib) produced anti-proliferative effects, indicating the lack of a class effect and of a role for COX-2. Our data emphasize again the outstanding anti-proliferative activity of celecoxib and its close structural analogue methylcelecoxib in colon carcinoma models in vitro and in vivo.