ABSTRACT
Signal transducer and activator of transcription 3 (STAT3) is a kind of signal transduction protein involved in cell proliferation, differentiation, apoptosis and other important physiological processes in response to a large number of cytokines and growth factors in cells. It has been shown that constitutive activation of STAT3 is closely associated with oncogenesis and tumorigenesis. Inhibition of aberrant STAT3 signaling has been one of promising strategies for the development of anti-neoplastic therapeutics. The review summarizes the latest progress of STAT3 inhibitors in recent years from the perspective of targeting N-terminal domain, DNA binding domain, SH2 domain and C-terminal transactivation domain of STAT3.
ABSTRACT
Ubiquitin-proteasome pathway (UPP) is one of the ways utilized for selective degradation of many proteins in cells, and the 20S proteasome takes the functional machinery where hydrolysis of targeted proteins takes place. Based on existing peptide inhibitors, a series of novel tripeptidic tetrazoles have been designed, synthesized, and the structures have been confirmed with 1H NMR, MS and elemental analysis. Among them, three compounds (6b, 6d and 6h) showed inhibitory activities of ChT-L of 20S proteasome.
Subject(s)
Biological Assay , Drug Design , Molecular Structure , Oligopeptides , Chemistry , Pharmacology , Proteasome Endopeptidase Complex , Chemistry , Proteasome Inhibitors , Chemistry , Pharmacology , Tetrazoles , Chemistry , PharmacologyABSTRACT
<p><b>AIM</b>To identify the main metabolites of hydrochloride 4-methyl-piperazine-1-carbodithioc acid 3-cyano-3,3-diphenyl-propyl ester (TM208) in rats.</p><p><b>METHODS</b>Rat feces, urine and plasma samples were collected after ig 500 mg x kg(-1) TM208, then the samples were extracted and concentrated using ethyl acetate. The treated samples were analyzed by HPLC-ESI/ITMSn. The structures of metabolites were elucidated according to the rules of drug metabolism and disposition in vivo and the characteristic fragmentation behaviors of TM208 in ESI-ITMSn.</p><p><b>RESULTS</b>Eight phase I metabolites were identified existing in rat feces, five of them were also found in rat urine and plasma, but no phase II metabolite was found.</p><p><b>CONCLUSION</b>The HPLC-ESI/ITMSn method is rapid, highly sensitive and specific and it is suitable for the identification of TM208 and its metabolites in rats.</p>
Subject(s)
Animals , Male , Rats , Antineoplastic Agents , Blood , Metabolism , Urine , Chromatography, High Pressure Liquid , Methods , Feces , Chemistry , Molecular Structure , Piperazines , Blood , Metabolism , Urine , Rats, Sprague-Dawley , Reproducibility of Results , Spectrometry, Mass, Electrospray Ionization , MethodsABSTRACT
<p><b>OBJECTIVE</b>To study the effect of cinobufagin (CBG) on HeLa cell proliferation, and to analyze its mechanism.</p><p><b>METHODS</b>Proliferation inhibition in vitro was evaluated by MTT and Sulforhodamine B (SRB) assays in several human tumor cell lines, including Bel-7402, HeLa, MCF-7, BGC-823 and HL60. The cycle of HeLa cells was analyzed by flow cytometry. Two-dimensional electrophoresis was applied to analyze the influence of CBG on HeLa cell proteomics.</p><p><b>RESULTS</b>CBG had inhibitory effects on proliferation of five human cancer cell lines, and the IC(50) values were 0.011 micromol/L (Bel-7402), 0.019 micromol/L (HeLa), 0.116 micromol/L (MCF-7), 0.149 micromol/L (BGC-823) and 1.369 micromol/L (HL60), respectively. HeLa and Bel-7402 cells were among the most sensitive. Flow cytometry assay indicated that the treatment of HeLa cells with various concentrations of CBG for 72 h was able to increase the cell number at G(2)/M phase, from 17.3% up to 35.6%. The results of two-dimensional electrophoresis showed that treatment of HeLa cells with 0.02 micromol/L CBG for 48 h resulted in apparent changes of certain small molecular weight (30,000 - 90,000) acidic proteins (pH 4 - 6).</p><p><b>CONCLUSION</b>Cinobufagin has significant inhibitory effect on growth of five human cancer cells in vitro. It may lead to cell cycle arrest of HeLa cells at G(2)/M phase. It can also change the expression of some small molecular acidic proteins in HeLa cells.</p>
Subject(s)
Humans , Antineoplastic Agents , Pharmacology , Bufanolides , Pharmacology , Cell Cycle , Cell Proliferation , Dose-Response Relationship, Drug , Drugs, Chinese Herbal , Pharmacology , HeLa Cells , Materia Medica , Pilot ProjectsABSTRACT
<p><b>OBJECTIVE</b>To investigate the molecular mechanisms of Z-ajoene mitosis blocking and telomerase inhibitory effects on HL-60 cells.</p><p><b>METHODS</b>Proliferation inhibition of HL-60 cell line was evaluated by MTT assay. Z-ajoene-induced mitotic blocking effect was investigated by flow cytometry. Immunoblotting analysis was used to determine cell cycle regulatory proteins. The telomerase activity of HL-60 cells was detected by TRAP-silver stain assay. Telomerase hTRT and TP1 mRNA level were determined by RT-PCR.</p><p><b>RESULTS</b>Z-ajoene displayed great proliferation inhibiting effect on HL-60 cells. Progressive increase in the percentage of mitotic block at G(2)/M phase was observed from 4 h to 12 h after treatment with 10 micromol/L Z-ajoene, with a peak at 10 h, which was 1.95 times higher than that in control. Z-ajoene also caused an increase in cyclin B1 accumulation and a decrease of p34(cdc2) expression. But Z-ajoene did not change the level of cyclin A. After treating with 10 micromol/L Z-ajoene for 24 h, the telomerase activity of HL-60 cells was also decreased in a dose-independent manner. Furthermore, telomerase hTRT and TP1 mRNA levels decreased after 10 micromol/L Z-ajoene treatment for 24 h.</p><p><b>CONCLUSION</b>The results suggest that Z-ajoene has potent anti-cancer activity, and that its inhibitory effect on telomerase activity and on cell growth might be the result of G(2)/M phase blocking.</p>