OBJECTIVETo investigate the possible mechanisms of nobiletin for anticancer by studying the inhibition effects of nobiletin on tubulin polymerization.

METHODIn vitro nobiletin was added into the tubulin polymerization-depolymerization system and the absorption values were recorded at 350 nm under 37 degrees C.

RESULTAs compared with controls, the absorption values in reaction system decreased significantly in nobiletin treatment groups. When nobiletin final concentrations in reaction system were 5.0, 7.5, 10.0 and 12.5 micromol x L(-1), the maximum absorption values were 0 130, 0.109, 0.086 and 0.071 with 16.7%, 30.1%, 44.9% and 54.5% of inhibition rate, respectively. The results suggested that nobiletin could inhibit tubulin polymerization.

CONCLUSIONThe inhibition effect of nobiletin on tubulin polymerization is the possible mechanism for anticancer.

Animals ; Flavones ; pharmacology ; Protein Binding ; drug effects ; Swine ; Tubulin ; chemistry ; metabolism ; Tubulin Modulators ; pharmacology

Microtubule is one of the key components of the cytoskeleton and plays an important role in the maintenance of cell shape and the process of signal transduction and mitosis. Due to the extreme importance of microtubule in the process of mitosis, tubulin becomes one of the most important targets for development of new anticancer drugs and tubulin inhibitors are used for the treatment of cancer nowadays. These inhibitors have antitumor activity by inhibiting or promoting the assembly of tubulin to microtubules and interfering the process of cell mitosis. This review summarized the research progress of the tubulin inhibitors, especially the introduction of the tubulin inhibitors of pharmacological activities and the progress of clinical research. Also, the development trend of these inhibitors is discussed.
Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Humans ; Microtubules ; drug effects ; metabolism ; Mitosis ; drug effects ; Molecular Structure ; Neoplasms ; drug therapy ; Stilbenes ; chemical synthesis ; chemistry ; pharmacology ; Structure-Activity Relationship ; Tubulin ; metabolism ; Tubulin Modulators ; chemical synthesis ; chemistry ; pharmacology

A series of noscapine analogues have been synthesized via 13-step reaction starting from 2-hydroxy-3-methoxybenzaldehyde. Anti-tumor activities of these compounds were evaluated against HL-60 cell lines in vitro by the standard MTT assay. It was found that most of these derivatives showed appreciable inhibitory activity against HL-60 and tubulin polymerization. The results also indicated that the potency of compound 31 is about three times more than that ofnoscapine against HL-60 cell line and tubulin polymerization. Moreover, it induced a massive accumulation of cells in G2/M phase. These results showed noscapine and its derivatives were worth to be intensively studied further.
Antineoplastic Agents ; chemical synthesis ; pharmacology ; Cell Cycle ; drug effects ; HL-60 Cells ; Humans ; Noscapine ; analogs & derivatives ; chemical synthesis ; pharmacology ; Polymerization ; drug effects ; Tubulin ; metabolism ; Tubulin Modulators ; chemical synthesis ; pharmacology

OBJECTIVETo investigate the differentiation induction effect of 2-methoxyestradiol (2ME2), an estrogen derivative on myeloma cell line CZ-1.

METHODSThe changes of CZ-1 cells in morphology, expression of surface CD49e and quantity of light chain secretion in the supernatant were observed when treated with 0.1 approximately 0.5 micromol/L 2ME2 for 48 h.

RESULTS2ME2 could induce differentiation of CZ-1 cells. The cells appeared decreased in size of nucleus, increased in cytoplasma, decreased in the ratio of nucleus to plasma, decreased in number or disappearance of nucleolus, and thickness and pyknosis of chromatin. The expression of CD49e was increased from (12.20 +/- 1.57)% to (24.80 +/- 1.26)% (P < 0.05). Light chain secretion in the supernatant was increased from (35.97 +/- 2.60) microg/ml to (79.67 +/- 1.88) microg/ml (P < 0.05).

CONCLUSIONLow concentrations of 2ME2 could induce differentiation of myeloma cell line CZ-1.

Cell Differentiation ; drug effects ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Estradiol ; analogs & derivatives ; pharmacology ; Flow Cytometry ; Humans ; Integrin alpha5 ; analysis ; Multiple Myeloma ; metabolism ; pathology ; Tubulin Modulators ; pharmacology

Ten pharmacophore models of beta-tubulin inhibitors were established from the training set of seventeen beta-tubulin inhibitors (two categories) with comformer analysis by using the Catalyst software. The optimal pharmacophore model with two hydrophobic units and two hydrogen bond acceptor units were confirmed (RMS = 0.43, Correl = 0.98, Weight = 2.06, Config = 15.97). This pharmacophore model is able to predict the activity of known beta-tubulin inhibitors and can be further used to identify structurally diverse compounds with higher activity.
Benzamides ; chemistry ; Computer-Aided Design ; Drug Design ; Models, Chemical ; Models, Molecular ; Molecular Conformation ; Molecular Structure ; Software ; Structure-Activity Relationship ; Tubulin Modulators ; chemistry ; Urea ; analogs & derivatives ; chemistry

PURPOSE: The effects on the side-branch (SB) ostium, following paclitaxel-coated balloon (PCB) treatment of de novo coronary lesions of main vessels have not been previously investigated. This study was aimed at evaluating the serial morphological changes of the SB ostium after PCB treatment of de novo coronary lesions of main vessels using optical coherence tomography (OCT). MATERIALS AND METHODS: This prospective, single-center observational study enrolled patients with de novo lesions, which were traversed by at least one SB (≥1.5 mm) and were treated with PCB. The SB ostium was evaluated with serial angiographic and OCT assessments pre- and post-procedure, and at 9-months follow-up. RESULTS: Sixteen main vessel lesions were successfully treated with PCB, and 26 SBs were included for analysis. Mean SB ostial lumen area increased at 9-months follow-up (0.92±0.68 mm2 pre-procedure, 1.03±0.77 mm2 post-procedure and 1.42±1.18 mm2 at 9-months). The SB ostial lumen area gain was 0.02±0.24 mm2 between pre- and post-procedure, 0.37±0.64 mm2 between post-procedure and 9-months, and 0.60±0.93 mm2 between pre-procedure and 9-months. The ostial lumen area increased by 3.9% [interquartile range (IQR) of -33.3 to 10.4%] between pre- and post-procedure, 52.1% (IQR of -0.7 to 77.3%) between post-procedure and 9-months and 76.1% (IQR of 18.2 to 86.6%) between pre-procedure and 9-months. CONCLUSION: PCB treatment of de novo coronary lesions of main vessels resulted in an increase in the SB ostial lumen area at 9-months.
Aged ; Angioplasty, Balloon, Coronary/*methods ; Coronary Angiography ; Coronary Stenosis/diagnosis/*therapy ; Coronary Vessels/*pathology ; *Drug-Eluting Stents/adverse effects ; Female ; Humans ; Male ; Middle Aged ; Paclitaxel/*administration & dosage ; Prospective Studies ; Tomography, Optical Coherence/*methods ; Treatment Outcome ; Tubulin Modulators/administration & dosage

Aged ; Cardiac Catheters ; Combined Modality Therapy ; Coronary Restenosis ; therapy ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Paclitaxel ; administration & dosage ; therapeutic use ; Percutaneous Coronary Intervention ; instrumentation ; Stents ; Treatment Outcome ; Tubulin Modulators ; administration & dosage ; therapeutic use

New colchicine analogs have been synthesized with the aim of developing stronger potential anticancer activities. Among the analogs, CT20126 has been previously reported to show immunosuppressive activities. Here, we report that CT20126 also shows potential anticancer effects via an unusual mechanism: the modulation of microtubule integrity and cell cycle arrest at the G2/M phase before apoptosis. When we treated COS-7 cells with CT20126 (5 muM), the normal thread-like microtubules were disrupted into tubulin dimers within 10 min and thereafter repolymerized into short, thick filaments. In contrast, cells treated with the same concentration of colchicine exhibited microtubule depolymerization after 20 min and never underwent repolymerization. Furthermore, optical density (OD) analysis (350 nm) with purified tubulin showed that CT20126 had a higher repolymerizing activity than that of Taxol, a potent microtubule-polymerizing agent. These results suggest that the effects of CT20126 on microtubule integrity differ from those of colchicine: the analog first destabilizes microtubules and then stabilizes the disrupted tubulins into short, thick polymers. Furthermore, CT20126 induced a greater level of apoptotic activity in Jurkat T cells than colchicine (assessed by G2/M arrest, caspase-3 activation and cell sorting). At 20 nM, CT20126 induced 47% apoptosis among Jurkat T cells, whereas colchicine induced only 33% apoptosis. Our results suggest that the colchicine analog CT20126 can potently induce apoptosis by disrupting microtubule integrity in a manner that differs from that of colchicine or Taxol.
Acetylation/drug effects ; Animals ; Apoptosis/*drug effects ; COS Cells ; Caspase 3/metabolism ; Cattle ; Cell Division/drug effects ; Cercopithecus aethiops ; Colchicine/*analogs & derivatives/chemistry/pharmacology ; Enzyme Activation/drug effects ; G2 Phase/drug effects ; Humans ; Jurkat Cells ; Microtubules/*metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Tubulin/metabolism ; Tubulin Modulators/chemistry/*pharmacology

OBJECTIVETo investigate the effect of trichostatin A (TSA)/paclitaxel on the growth and apoptosis in human lung adenocarcinoma cell line A549 cells.

METHODSHuman lung adenocarcinoma A549 cells were cultured in DMEM in the presence of paclitaxel and the histone deacetylase inhibitor trichostatin A, and the growth curve was obtained by trypan-blue exclusion assay and cell count. Apoptosis was assessed using Hoechst 33258 staining and flow cytometry, and cell cycle was detected by flow cytometry analysis. The proteins of PARP, caspase-3, survivin and tubulin acetylation were detected by Western blotting.

RESULTSSignificant growth reduction was observed in the A549 cells following treatment with paclitaxel or the histone deacetylase inhibitor TSA. The combined treatment with TSA/paclitaxel caused the highest inhibition of cell growth. The apoptosis rate of A549 cells treated with TSA or paclitaxel for 24 hours was (17.6 ± 1.8)% and (39.2 ± 3.7)%, respectively, but a significantly higher apoptosis rate was (64.2 ± 4.2)% was induced by combined treatment with TSA and paclitaxel. In contrast with the control group, the cell cycle was markedly arrested at G2/M phase in the TSA and paclitaxel group (P < 0.05). The Western blot analysis demonstrated that treatment with TSA/paclitaxel led to a synergistic increase of acetylated tubulin, PARP and caspase-3, and reduced the expression of survivin.

CONCLUSIONTSA or paclitaxel alone can inhibit the cell growth and induce apoptosis, and the combination of TSA and paclitaxel exerts a synergistic effect on the growth and apoptosis in lung adenocarcinoma cells.

Acetylation ; Adenocarcinoma ; metabolism ; pathology ; Antineoplastic Agents, Phytogenic ; pharmacology ; Apoptosis ; drug effects ; Caspase 3 ; metabolism ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Drug Synergism ; Histone Deacetylase Inhibitors ; pharmacology ; Humans ; Hydroxamic Acids ; pharmacology ; Inhibitor of Apoptosis Proteins ; metabolism ; Lung Neoplasms ; metabolism ; pathology ; Paclitaxel ; pharmacology ; Poly(ADP-ribose) Polymerases ; metabolism ; Tubulin ; metabolism ; Tubulin Modulators ; pharmacology

Podophyllotoxone (1) was isolated from the roots of Dysosma versipellis. The structure was determined by spectroscopic analysis in combination with single-crystal X-ray analysis. The absolute configuration of compound 1 was assigned based on the Flack parameter. It showed significant inhibitory activities against human prostate cancer cells PC3 and DU145 with IC50 values being 14.7 and 20.6 μmol·L(-1), respectively. It also arrested the cells at G2/M phase. Tubulin polymerization assay showed that it inhibited the tubulin polymerization in a dose-dependent manner, and molecular docking analysis revealed a different binding mode with tubulin as compared with those known tubulin inhibitors.
Antineoplastic Agents ; chemistry ; pharmacology ; Berberidaceae ; chemistry ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; G2 Phase ; drug effects ; Humans ; Hydrogen Bonding ; drug effects ; Male ; Molecular Conformation ; Molecular Docking Simulation ; Phytotherapy ; Plant Extracts ; chemistry ; pharmacology ; Plant Roots ; chemistry ; Podophyllotoxin ; chemistry ; pharmacology ; Polymerization ; Prostatic Neoplasms ; drug therapy ; Tubulin ; drug effects ; Tubulin Modulators ; pharmacology