Biochemical pharmacology
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Biochemical pharmacology · Sep 2010
ReviewMolecularly targeted therapy in hepatocellular carcinoma.
With an annual incidence of over 660,000 deaths, hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally. This disease is often diagnosed at an advanced stage, when potentially curative therapies are not feasible. HCC is highly resistant to conventional systemic therapies and prognosis for advanced HCC patients remains poor. ⋯ A number of strategies including monoclonal antibodies and tyrosine kinase inhibitors such as erlotinib, sunitinib, vandetanib, cediranib, brivanib, foretinib, and dovitinib have been developed and tested in various phases of clinical trials. The successful development of these novel targeted agents in the future will be dependent on the selection of patient populations that are most likely to derive clinical benefit, optimization of the dose used and schedules, and investigation of combined therapies. This review describes evolving molecular targeted agents, their common adverse side effects, and its potential use in management of HCC.
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Biochemical pharmacology · Jun 2010
The dopamine receptor D2 agonist bromocriptine inhibits glucose-stimulated insulin secretion by direct activation of the alpha2-adrenergic receptors in beta cells.
Treatment with the dopamine receptor D2 (DRD2) agonist bromocriptine improves metabolic features in obese patients with type 2 diabetes by a still unknown mechanism. In the present study, we investigated the acute effect of bromocriptine and its underlying mechanism(s) on insulin secretion both in vivo and in vitro. For this purpose, C57Bl6/J mice were subjected to an intraperitoneal glucose tolerance test (ipGTT) and a hyperglycemic (HG) clamp 60min after a single injection of bromocriptine or placebo. ⋯ Surprisingly, the DRD2 antagonist domperidone did not counteract the effect of bromocriptine on GSIS, whereas yohimbine, an antagonist of the alpha2-adrenergic receptors, completely abolished bromocriptine-induced inhibition of GSIS. In conclusion, acute administration of bromocriptine inhibits GSIS by a DRD2-independent mechanism involving direct activation of the pancreatic alpha2-adrenergic receptors. We suggest that treatment with bromocriptine promotes beta cells rest, thereby preventing long-lasting hypersecretion of insulin and subsequent beta cell failure.
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Biochemical pharmacology · May 2010
BFPP, a phloroglucinol derivative, induces cell apoptosis in human chondrosarcoma cells through endoplasmic reticulum stress.
Chondrosarcoma is a malignant primary bone tumor that responds poorly to both chemotherapy and radiation therapy. This study is the first to investigate the anticancer effects of the new phloroglucinol derivative (2,4-bis(2-fluorophenylacetyl)phloroglucinol; BFPP) in human chondrosarcoma cells. BFPP induced cell apoptosis in two human chondrosarcoma cell lines, JJ012 and SW1353 but not in primary chondrocytes. ⋯ Transfection of cells with GRP78 or calpain siRNA reduced BFPP-mediated cell apoptosis in JJ012 cells. Importantly, animal studies have revealed a dramatic 50% reduction in tumor volume after 21 days of treatment. This study demonstrates novel anticancer activity of BFPP against human chondrosarcoma cells and in murine tumor models.
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Biochemical pharmacology · May 2010
St. John's Wort reduces neuropathic pain through a hypericin-mediated inhibition of the protein kinase Cgamma and epsilon activity.
Current pharmacological treatments for neuropathic pain have limited efficacy and severe side-effect limitations. St. John's Wort (SJW) is a medicinal plant, mainly used as antidepressant, with a favourable side-effect profile. ⋯ Furthermore, SJW showed a dual mechanism of action since hyperforin antinociception involves an opioid-dependent pathway. Rats undergoing treatment with SJW and purified components did not show any behavioural side effects or signs of altered locomotor activity. Our results indicate SJW as a prolonged antihyperalgesic treatment through inhibition of PKC isoforms and their phosphorylation.
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Biochemical pharmacology · Nov 2009
Inhibitory mechanisms of heterocyclic carboxaldehyde thiosemicabazones for two forms of human ribonucleotide reductase.
Two forms of ribonucleotide reductase (RR), consisting of M1 with M2 subunits and M1 with p53R2 subunits, are involved in DNA replication and damage repair, respectively. 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3AP), one of the heterocyclic carboxaldehyde thiosemicabazones (HCTs), is a potent RR inhibitor in clinical trial for cancer treatment. In this study, 3AP and its 7 derivatives showed 100-1000-fold higher inhibitory potency on KB nasopharyngeal carcinoma cells than hydroxyurea and were fully active against hydroxyurea- and gemcitabine-resistant KB cells. In vitro RR assays using two recombinant RRs showed that all 8 HCTs decreased the activity of both RRs in a dose-dependent manner and the efficiency was compatible with that on cell proliferation inhibition. ⋯ Electron paramagnetic resonance measurements demonstrated that these HCTs generated reactive oxygen species with ferrous iron, which quenched the diiron-tyrosyl radical co-factor of the small subunits and hence the enzyme activity. While the ROS may be a common mediator responsible for the potent activity of the HCTs, the different characteristics of the small subunit proteins are probably associated with the subunit-selectivity of inhibition. Better understanding of the mechanism of action of RR inhibition may improve design of new potent and subunit-selective RR inhibitors for cancer therapy.