Biochemical pharmacology
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Biochemical pharmacology · Jun 2008
Magnolol elicits activation of the extracellular signal-regulated kinase pathway by inducing p27KIP1-mediated G2/M-phase cell cycle arrest in human urinary bladder cancer 5637 cells.
Magnolol has been reported to play a role in antitumor activity. However, the relevant pathway integrating cell cycle regulation and signaling pathways involved in growth inhibition in cancer cells remains to be identified. In the present study, magnolol treatment of these cells resulted in significant dose-dependent growth inhibition together with apoptosis, G1- and G2/M-phase cell cycle arrest at a 60 microM (IC50) dose in 5637 bladder cancer cells. ⋯ Finally, the magnolol-induced reduction in cell proliferation and G2/M cell cycle proteins was also abolished in the presence of RasN17 and RafS621A mutant genes. These data demonstrate that the Ras/Raf/ERK pathway participates in p27KIP1 induction, leading to a decrease in the levels of cyclin B1/Cdc2 complexes and magnolol-dependent inhibition of cell growth. Overall, these novel findings concerning the molecular mechanisms of magnolol in 5637 bladder cancer cells provide a theoretical basis for therapeutic treatment of malignancies.
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Biochemical pharmacology · Dec 2007
Anti-tumor potential of 15,16-dihydrotanshinone I against breast adenocarcinoma through inducing G1 arrest and apoptosis.
Chemotherapeutic drugs are usually designed to induce cancer cell death via cell cycle arrest and/or apoptosis pathways. In this study, we used the chemical drug 15,16-dihydrotanshinone I (DHTS) to inhibit breast cancer cell proliferation and tumor growth, and investigate the underlying molecular mechanisms. Human breast cancer cell lines MCF-7 and MDA-MB-231 were both used in this study, and DHTS was found to significantly decrease cell proliferation by a dose-dependent manner in both cells. ⋯ The fact that DHTS-induced apoptosis could be blocked by pretreating cells with pan-caspase inhibitor confirmed that it is mediated through activation of the caspase-3-dependent pathway. In a nude mice xenograft experiment, DHTS significantly inhibited the tumor growth of MDA-MB-231 cells. Taken together, these results suggest that DHTS can inhibit human breast cancer cell proliferation and tumor growth, and might have potential chemotherapeutic applications.
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Biochemical pharmacology · Oct 2007
A-366833: a novel nicotinonitrile-substituted 3,6-diazabicyclo[3.2.0]-heptane alpha4beta2 nicotinic acetylcholine receptor selective agonist: Synthesis, analgesic efficacy and tolerability profile in animal models.
5-[(1R,5S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile (A-366833) is a novel nicotinic acetylcholine receptor (nAChR) ligand that binds to the agonist-binding site ([3H]-cytisine) with Ki value of 3.1 nM and exhibits agonist selectivity at alpha4beta2 nAChR relative to the alpha3beta4 nAChR subtype. The analgesic effects of A-366833 were examined across a variety of animal models including the mouse model of writhing pain (abdominal constriction), the rat models of acute thermal (hot box), persistent chemical (formalin) and neuropathic (spinal nerve ligation, SNL) pain. In the abdominal constriction model, A-366833 was effective at doses ranging from 0.062 to 0.62 micromol/kg (i.p.). ⋯ Pharmacokinetic investigations of A-366833 in rat revealed moderate brain:plasma distribution, half-life of 1.5h and excellent oral bioavailability of 73%. Comparison of peak plasma levels at the minimal effective doses across rat models of acute thermal pain, formalin and SNL with the maximal exposure that does not evoke emesis in ferret revealed therapeutic margins ranging from 6- to 22-fold. These studies indicate that compounds like A-366833 with improved agonist selectivity at alpha4beta2 vs. alpha3beta4 nAChR can elicit a broad spectrum of analgesic efficacy without concurrent adverse effects.
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Biochemical pharmacology · Jun 2007
Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes.
Involvement of cytochrome P450 (P450 or CYP) 2C19, 2C9, and 3A4 in N-oxidation of voriconazole, a new triazole antifungal agent, has been demonstrated using human liver microsomes. To confirm the precise roles of P450 isoforms in voriconazole clearance in individuals, we investigated the oxidative metabolism of voriconazole catalyzed by recombinant P450s as well as human liver microsomes genotyped for the CYP2C19 gene. Among recombinant P450 isoforms using Escherichia coli expression systems, CYP2C19 and CYP3A4 had voriconazole N-oxidation activities, but not CYP2C9. ⋯ CYP3A4 produced a new methyl hydroxylated metabolite from voriconazole, detected by LC/UV and LC/MS/MS and confirmed by 1H and 13C NMR analyses, with K(m) and V(max) values of 11+/-3 microM and 0.10+/-0.01 nmol/min/nmol CYP3A4. The voriconazole 4-hydroxylation to N-oxidation metabolic ratios in liver microsomes from the wild-type CYP2C19*1/*1 individuals (0.07) were lower than those observed in other genotypes (0.20-0.27) at a substrate concentration of 25 microM based on the reported clinical plasma level. These results suggest that the CYP2C19 genotype, but not CYP2C9 genotype, would be evaluated as a key factor in the pharmacokinetics of voriconazole and that 4-hydroxyvoriconazole formation may become an important pathway for voriconazole metabolism in individuals with poor CYP2C19 catalytic function.
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Biochemical pharmacology · May 2007
Novel agonistic action of mustard oil on recombinant and endogenous porcine transient receptor potential V1 (pTRPV1) channels.
Neurogenic components play a crucial role in inflammation and nociception. Mustard oil (MO) is a pungent plant extract from mustard seed, horseradish and wasabi, the main constituent of which is allylisothiocyanate. We have characterized the action of MO on transient receptor potential V1 (TRPV1), a key receptor of signal transduction pathways in the nociceptive system, using fura-2-based [Ca(2+)](i) imaging and the patch-clamp technique in a heterologous expression system and sensory neurons. ⋯ Among DRG neurons responding to MO, 85% were also sensitive to capsaicin. The present data indicate that MO is a novel agonist of TRPV1 channels, and suggest that the action of MO in vivo may be partly mediated via TRPV1. These results provide an insight into the TRPV1-mediated effects of MO on inflammation and hyperalgesia.