OBJECTIVETo investigate the effect of tyrosine kinase inhibitor ZD6474 (Vandetanib) on the proliferative inhibition of K562 cells and its derived imatinib-resistant K562/G cells and its mechanism.

METHODSImatinib-resistant K562/G cells were obtained by culturing cells in gradually increasing concentrations of imatinib. The changed factors related to drug-resistance were tested by Western blot. ZD6474 and imatinib affected K562/G and parental K562 cells proliferation were analyzed by WST assay. Flow cytometry was used to analyze cell cycle. Direct inhibition of Src activity by ZD6474 was measured by a colorimetric ELISA assay with recombinant human Src kinase.

RESULTS10 µmol/L imatinib failed to inhibit K562/G cells proliferation or induce cell cycle arrest. Compared with that in parental K562 cells, there were marked high levels of p-Src and Src protein in K562/G cells. The expression of Bcl-2 and p-STAT3 also increased in K562/G cells. After 48 hours incubation, the IC(50) values of ZD6474 in K562 and K562/G cells were 1.61 µmol/L and 3.18 µmol/L, respectively. ZD6474 treatment caused accumulation of cells in the G(0)/G(1) fraction and cell apoptosis in K562 and K562/G cells. ZD6474 decreased the expression of p-Src and Src at post-transcriptional level. Moreover, ZD6474 increased the ratio of Bax/Bcl-2 and decreased the expression of p-STAT3 at the same concentration for inducing apoptosis.

CONCLUSIONSZD6474 is effective in inhibiting the proliferation of imatinib-resistant K562/G cells and parental K562 cells, and induces their apoptasis by significant inhibition of Src kinase activity. Our study provides a reliable experimental basis for chronic myeloid leukemia treatment with ZD6474.

Apoptosis ; drug effects ; Benzamides ; pharmacology ; Humans ; Imatinib Mesylate ; K562 Cells ; Piperazines ; pharmacology ; Pyrimidines ; pharmacology

To explore novel histone deacetylase (HDACs) inhibitors with anti-tumor activity, MS-275, a HDACs inhibitor, was prepared and used as a lead compound to design new N-substituted benzamide derivatives. MS-275 and eleven target compounds were obtained, and their structures were confirmed by 1H NMR and HR-MS individually. The results showed that the activity of compound 9d was equal to MS-275 in HDACs inhibition tests in vitro and worthy of further investigation. Compound 5c, 5d and 9c displayed obvious dose-effect relationship, which possessed moderate HDACs inhibitory activities. Ten compounds except 9e had selective inhibitory activities on Hut78.
Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Benzamides ; chemical synthesis ; chemistry ; pharmacology ; Cell Line, Tumor ; Humans

To explore novel antifatigue agents targeting with AMPA receptor, 10 compounds were synthesized and their structures were confirmed by 1H NMR, ESI-MS and elemental analysis. 1-BCP was treated as the leading compound. The antifatigue activities were evaluated by weight-loaded forced swimming test, and the AMPA receptor binding affinities were tested with radioligand receptor binding assays. The results unveiled that 5b appeared to possess potent antifatigue activities and high affinity with AMPA receptor, which deserved further studies.
Animals ; Benzamides ; chemistry ; pharmacology ; Dioxoles ; chemistry ; pharmacology ; Fatigue ; prevention & control ; Piperidines ; chemistry ; pharmacology ; Radioligand Assay ; Receptors, AMPA ; metabolism ; Swimming

OBJECTIVE: To investigate the effects of chidamide combined with anti-myeloma drugs on the proliferation and apoptosis of myeloma cells. METHODS: The proliferation inhibition of the cells was detected by CCK-8 method, and flow cytometry was used to detected the apoptosis of the cells. RESULTS: Chidamide could inhibit the proliferation of myeloma cells and promote the apoptosis of primary myeloma plasma cells in a time- and dose-dependent manner (P<0.05). In NCI-H929 cell line, chidamide combined with low-dose bortezomib and lenalidomide showed synergistic effect, while combined with dexamethasone and pomalidomide showed additive effect. In MM.1s cell line, chidamide combined with bortezomib, dexamethasone, lenalidomide and pomalidomide all showed synergistic effects. CONCLUSION Chidamide inhibits proliferation of myeloma cells in a time- and dose-dependent manner and promotes apoptosis of primary myeloma plasma cells. Furthermore, it can enhance the inhibitory effect of anti-myeloma drugs.
Aminopyridines ; Apoptosis ; Benzamides ; Bortezomib/pharmacology* ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Multiple Myeloma ; Pharmaceutical Preparations

OBJECTIVETo compare the bronchofilating and antiallergic effects with piclamilast with ciclamilast, the second-generation phosphodiesterase 4 (PDE4) selective inhibitors.

METHODSEffects of piclamilast and ciclamilast on airway smooth muscle (ASM) at resting tension, carbachol-induced contraction and the synergistic effect of two agents on isoproterenol-induced bronchorelaxation were evaluated in the isolated tracheal strips of guinea pig in a cumulative manner in vitro. Slow reaction substance of anaphylaxis (SRS-A) release from lung tissues of the sensitized guinea pigs after antigen challenge was examined by bioassay. Antiallergic effect of piclamilast, ciclamilast and rolipram on the isolated ASM of sensitized guinea pigs were evaluated with Schultz-Dale reaction.

RESULTSPiclamilast and ciclamilast showed bronchorelaxant effect in ASM at resting tension. EC50 values of piclamilast and ciclamilast were 1.00 x 10(-5) mol/L and 0.84 x 10(-5) mol/L. Piclamilast and ciclamilast could both enhance the bronchodilating effect of isoproterenol in the isolated ASM of guinea pig, reduce the amount of SRS-A released from lung tissues of the sensitized guinea pigs and also inhibit ovalbumin (OA)-induced bronchoconstruction (Schultz-Dale reaction).

CONCLUSIONThe results indicate the bronchodilating effect of ciclamilast is as potent as piclamilast, but the antiallergic effect of ciclamilast is significantly more potent than that of piclamilast.

Animals ; Anti-Allergic Agents ; pharmacology ; Benzamides ; pharmacology ; Bronchodilator Agents ; pharmacology ; Dose-Response Relationship, Drug ; Female ; Guinea Pigs ; In Vitro Techniques ; Isoproterenol ; pharmacology ; Male ; Phosphodiesterase Inhibitors ; pharmacology ; Pyridines ; pharmacology

OBJECTIVETo study the inhibitory activities of 3-trifluoromethyl benzamide derivatives against the entry of H5N1 influenza viruses.

METHODSThe lead compound was structurally modified to obtain 3 compounds with inhibitory activities against H5N1 influenza viruses. Specs compound librany was screened and 4 compounds were identified to have such inhibitory activities. The inhibitory activities of these compounds were tested at a celluar level against H5N1 influenza viruses.

RESULTS AND CONCLUSIONThe compounds 1a, 1b, 1e and 1f showed signifcant inhibitory activities against the entry of A/AnHui/1/2005 pseudovirus into the target cells with an IC50 value of 4.7 ± 0.3 µmol/L.

Antiviral Agents ; pharmacology ; Benzamides ; pharmacology ; Humans ; Influenza A Virus, H5N1 Subtype ; drug effects ; physiology ; Influenza, Human ; Virus Internalization ; drug effects

PURPOSE: Gastric emptying has been evaluated by scintigraphy in spite of its limitations of time consumption, cost, and danger of radioisotope. Endoscopy is a simple technique, however, its validation for gastric emptying and quantification of food has not yet been investigated. The aim of our study was to assess endoscopic gastric emptying compared with scintigraphy and radiopaque markers (ROMs) studies. We also investigated the effect of a single dose of mosapride on gastric emptying. MATERIALS AND METHODS: Fifteen healthy volunteers underwent scintigraphy. Next day, subjects received a standard solid meal with ROMs and underwent endoscopy and simple abdomen X-ray after 3 hrs. After one week, the same procedure was repeated after ingestion of mosapride (5 mg for group 1, n = 8; 10 mg for group 2, n = 7) 15 min before the meal. Quantification of gastric residue by endoscopy was scored from 0 to 3, and the scores were added up. RESULTS: All subjects completed the study without any complication. The gastric emptying rate [T1/2 (min)] was in normal range (65.6 +/- 12.6 min). Endoscopic gastric emptying was correlated significantly with gastric clearance of ROMs (r = 0.627, p = 0.012). Endoscopic gastric emptying and gastric clearance of ROMs after administration of mosapride showed significant differences in the 10 mg group (p < 0.05). CONCLUSION: Endoscopy can evaluate gastric emptying safely and simply on an outpatient basis. A 10 mg dose of mosapride enhanced gastric emptying, assessed by both endoscopy and ROMs.
Adult ; Benzamides/*pharmacology ; Endoscopy/*methods ; Female ; Gastric Emptying/*drug effects ; Gastrointestinal Agents/*pharmacology ; Humans ; Male ; Middle Aged ; Morpholines/*pharmacology ; Radionuclide Imaging/*methods ; Stomach/radiography/radionuclide imaging ; Young Adult

Mosapride citrate (Mosapride) is a new prokinetic agent that enhances the gastrointestinal (GI) motility by stimulation of 5-HT4 receptors. This agent stimulates acetylcholine release from enteric cholinergic neurons in the GI wall. It was reported in several studies that mosapride selectively enhanced the upper, but not lower, GI motor activity. However, in these studies other 5-HT4 receptor agonists exerted stimulating effects on the motility of the colon. Moreover, it is well known that the receptors of 5-HT4 are also located in the colon. The purpose of this study was to estimate the effect of mosapride on the motility of the stomach, ileum and colon in the guinea pig and to investigate whether or not mosapride influenced the colonic motility. Mosapride significantly increased the amplitude of the contraction waves in the guinea pig stomach by electrical stimulation. In addition, it significantly increased the number of peaks, the area under the curve and the propagation velocity of the peristaltic contraction of the guinea pig ileum in a concentration dependent fashion. Mosapride also significantly shortened the transit time of the guinea pig colon. Accordingly, we concluded that mosapride exerted prokinetic effect on the entire GI tract of the guinea pig. Based on the possibility of similar results in humans, we suggest the potential use of mosapride for lower GI motor disorders such as constipation and upper GI motor disorders such as gastroesophageal reflex disease or gastroparesis.
Animals ; Benzamides/*pharmacology ; Colon/*drug effects ; Gastrointestinal Agents/*pharmacology ; Gastrointestinal Motility/*drug effects ; Guinea Pigs ; Ileum/*drug effects ; Morpholines/*pharmacology ; Stomach/*drug effects ; Support, Non-U.S. Gov't

STI571 is a new antileukemia agent targeting BCR-ABL tyrosine kinase and successfully used in treatment of leukemia patients. Despite strong efficacy of the tyrosine kinase inhibitor STI571, resistance has been observed in a significant proportion of leukemia patients. This review focuses on the diverse mechanisms of ST1571 resistance and its preventive measures.
Animals ; Antineoplastic Agents ; pharmacology ; Benzamides ; Drug Resistance, Neoplasm ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; Piperazines ; pharmacology ; Pyrimidines ; pharmacology

Adult ; Aged ; Benzamides ; pharmacology ; Drug Resistance, Neoplasm ; genetics ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; genetics ; Middle Aged ; Piperazines ; pharmacology ; Point Mutation ; Pyrimidines ; pharmacology