This study is to explore new lead compounds by inhibition of Pin1 for anticancer therapy using temperature sensitive mutants. As Pin1 is conserved from yeast to human, we established a high-throughput screening method for Pin1 inhibitors, which employed yeast assay. This method led to the identification of one potent hits, 8-11. In vitro, 8-11 inhibited purified Pin1 enzyme activity with IC50 of (10.40 +/- 1.68) micromol x L(-1), induced G1 phase arrest and apoptosis, showed inhibitory effects on a series of cancer cell proliferation, reduced Cyclin D1 expression, was defined as reciprocally matched for protein-ligand complex in virtual docking analysis and reduced cell migration ability. In vivo, we could observe reduction of tumor volume after treatment with 8-11 in xenograft mice compared with vehicle DMSO treatment. Altogether, these results provide for the first time the involvement of 8-11 in the anticancer activity against Pin1.
Animals ; Apoptosis ; drug effects ; Cell Proliferation ; drug effects ; Cyclin D1 ; metabolism ; Drug Screening Assays, Antitumor ; methods ; G1 Phase ; High-Throughput Screening Assays ; methods ; Humans ; Mice ; NIMA-Interacting Peptidylprolyl Isomerase ; Neoplasms ; pathology ; Peptidylprolyl Isomerase ; antagonists & inhibitors ; Temperature ; Xenograft Model Antitumor Assays ; Yeasts

OBJECTIVETo study the association of drug sensitivity of rat hepatocarcinoma cells and bone marrow mesenchymal stem cells (MSCs) to 5 antitumor drug with different antitumor mechanisms with tumorigenicity of the hepatocarcinoma cells in nude mice.

METHODSPrimary liver carcinoma was induced with diethylnitrosamine in rats, and the tumor cells and MSCs were obtained from 10 of the rats. The inhibition ratio of the hepatocarcinoma cells and MSCs following treatment with the 5 drugs were measured by MTT assay. The weight of the tumor in nude mice resulting from the injection of the isolated tumor cells treated with the 5 anticancer drugs was measured 6 weeks after implantation. For each anticancer drug, the difference in the inhibition ratio of the anticancer drugs against the hepatocarcinoma cells and MSCs, and he correlation of the inhibition ratio of the anticancer drugs with implanted tumor weight were analyzed.

RESULTSNo correlation was found between the inhibition ratio of the 5 anticancer drugs against the hepatocarcinoma cells and the tumor weight of nude mice, but a significant negative correlation was identified between the inhibition ratio of the MSCs and the tumor weight.

CONCLUSIONMSCs have similar drug resistance mechanism to the tumor stem cells. The inhibition ratio of the anticancer drugs against the MSCs can help evaluate the invasion potential of hepatocarcinoma cells.

Animals ; Antineoplastic Agents ; pharmacology ; Cell Survival ; drug effects ; Drug Screening Assays, Antitumor ; methods ; Liver Neoplasms, Experimental ; pathology ; prevention & control ; Male ; Mesenchymal Stromal Cells ; drug effects ; pathology ; Mice ; Mice, Nude ; Neoplastic Stem Cells ; drug effects ; pathology ; Rats ; Rats, Sprague-Dawley ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; methods

According to drug design flattening principle and using podophyllotoxin or 4'-demethylepipodophyllotoxin and aldehydes as starting material,a series of podophyllotoxin derivatives containing an imine structure with low toxicity were highly effective synthesized. Nine target compounds were successfully synthesized,and their structures were confirmed by ~1H-NMR,HR-ESI-MS and melting point data analysis. Using etoposide as positive control drug,nine target compounds were screened for cytotoxicity against He La cells in vitro by MTT method. The antitumor activity screening results showed that compound 6 b,6 d,6 e,6 f,6 g,6 i exhibited higher inhibitory rate against He La cells than those of control drug VP-16. It provides some practical reference value for the further development on the structure modification of podophyllotoxin and study on anti-tumor activity.
Antineoplastic Agents/pharmacology* ; Drug Design ; Drug Screening Assays, Antitumor ; Podophyllotoxin/pharmacology* ; Structure-Activity Relationship

This is to report the screening, extracting and validating antitumor components and compounds from Stellera chamaejasme L. under the case of discrete distribution of active data. In this work, different components from Stellera chamaejasme L. were collected by HPD macroporous resin and polyamide resin column, and their antitumor activity on A549 were tested by MTT assay. Activity results indicate that activity of components at 30-39 min is more potent than that of Stellera chamaejasme L. extract, and the activity of components at 33.97 min is equivalent to positive drug, cis-platinum at 100 microg x mL(-1), but with totally different mode of action. Under the case of discrete activity, the weight analysis is capable of screening active components and compounds from natural products.
Antineoplastic Agents, Phytogenic ; pharmacology ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Humans ; Thymelaeaceae ; chemistry

OBJECTIVETo develop a fluorescence imaging-based novel system for quick screening of antitumor compounds in vitro.

METHODSThe antitumor activity of 26 components from Lindera aggregate were determined by relative number of viable cell labelled with fluorescein diacetate (FDA) in multiwell plates after exposure to these 26 different components. Then, the linearity and precision of this method were validated. The structures of active compounds in components with strong antitumor activity were deduced by LC/MS.

RESULTSThe linearity of this method for cells stained with FDA was validated (r² = 0.9858) in the range of 0-10⁴ cells per well, and the in-plate precision was 9.41 %. Two of 26 components from Lindera aggregate showed significant inhibition effect on proliferation of HepG2 cells (inhibition rate >90%).

CONCLUSIONThis proposed rapid and reliable approach can be used for screening compounds with antitumor activity from Traditional Chinese Medicine in vitro. The major active compound of Lindera aggregate was putatively identified as norboldine by LC/MS analysis.

Antineoplastic Agents, Phytogenic ; pharmacology ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; methods ; Fluorescence ; Humans

The present study was designed to identify potent anti-tumor compounds from a series of new longistylin C derivatives. Ten longistylin C derivatives were synthesized and their structures were confirmed by (1)H NMR, MS, and elemental analyses. Their cytotoxicity in vitro against three human cancer cell lines (A549, HepG2, and MCF-7) were evaluated by the MTT assay. Among these compounds, DT-6 and DT-9 displayed much better cytotoxicity against A549, HepG2, and MCF-7 cells, DT-1 exhibited selective cytotoxicity against HepG2, and the structure-activity relationships were investigated. In conclusion, Compounds DT-6 and DT-9 may serve as potential lead compounds for the discovery of new anti-cancer drugs.
Antineoplastic Agents ; chemical synthesis ; pharmacology ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Humans ; Structure-Activity Relationship

In this study, we explored the feasibility of biotin-mediated modified polymeric micelles for pancreatic cancer targeted photodynamic therapy. Poly (ethylene glycol)-distearoyl phosphatidyl ethanolamine (mPEG2000-DSPE) served as the drug-loaded material, biotin-poly(ethylene glycol)-distearoyl phosphatidyl ethanolamine (Biotin-PEG3400-DSPE) as the functional material and the polymeric micelles were prepared by a thin-film hydration method. The targeting capability of micelles was investigated by cell uptake assay in vitro and fluorescence imaging in vivo and the amounts of Biotin-PEG-DSPE were optimized accordingly. Hypocrellin B (HB), a novel photosensitizer was then encapsulated in biotinylated polymeric micelles and the anti-tumor efficacy was evaluated systemically in vitro and in vivo. The results showed that micelles with 5 mol % Biotin-PEG-DSPE demonstrated the best targeting capability than those with 20 mol % or 0.5 mol % of corresponding materials. This formulation has a small particle size [mean diameter of (36.74 ± 2.16) nm] with a homogeneous distribution and high encapsulation efficiency (80.06 ± 0.19) %. The following pharmacodynamics assays showed that the biotinylated micelles significantly enhanced the cytotoxicity of HB against tumor cells in vitro and inhibited tumor growth in vivo, suggesting a promising potential of this formulation for treatment of pancreatic cancer, especially those poorly permeable, or insensitive to radiotherapy and chemotherapy.
Animals ; Antineoplastic Agents ; chemistry ; Biotin ; Drug Carriers ; chemistry ; Drug Screening Assays, Antitumor ; Humans ; Micelles ; Pancreatic Neoplasms ; drug therapy ; Photochemotherapy

No abstract available
Antineoplastic Agents/*therapeutic use ; Drug Screening Assays, Antitumor ; *Gene Expression ; Humans ; Neoplasms/drug therapy/*genetics ; Treatment Outcome

PURPOSE: ATP-based chemotherapy response assay (ATP-CRA) is a well-documented and validated technology that can individualize chemotherapy. This study was undertaken to assess the usefulness of ATP-CRA in advanced colorectal cancer (CRC) patients receiving adjuvant chemotherapy. METHODS: A total of 136 patients with curative resection between January 2006 and April 2014 were evaluated using ATP-CRA. Patients received either the FOLFOX or Mayo clinic regimen chemotherapy following assay results. The sensitive-group (S-group) was defined as a drug-producing ≥ 40% reduction in ATP, and the resistant-group (R-group) as an ATP reduction of < 40%. These 2 groups were further subdivided to produce 4 subgroups: the FOLFOX sensitive subgroup (the FS subgroup [n = 65]), the Mayo sensitive subgroup (the MS subgroup [n = 40]), the FOLFOX resistant subgroup (the FR subgroup [n = 10]), and the Mayo resistant subgroup (the MR subgroup [n = 21]). Clinical responses and survival results were compared for both treatment regimens. RESULTS: The FS and MS subgroups showed a better disease-free survival rate (29% vs. 40%, 35% vs. 47.6%) and overall survival rate (92.3% vs. 80.0%, 87.5% vs. 76.2%) than FR and MR subgroups. The FS and MS subgroups showed a longer time to relapse (20.2 months vs. 9.5 months, 17.6 months vs. 16.4 months) than the FR and MR subgroups. CONCLUSION: ATP-CRA tailored-chemotherapy has the potential to provide a survival benefit in resectable advanced CRC.
Adenosine Triphosphate ; Adenosine ; Chemotherapy, Adjuvant ; Colorectal Neoplasms ; Disease-Free Survival ; Drug Screening Assays, Antitumor ; Drug Therapy ; Humans ; Recurrence ; Survival Rate

The study is to report the establishment of a method of screening the antitumor compounds based on the dynamic bio-response profile of cells to make up for the shortages of conventional end-point tests such as tedious operation and low sensitivity. Based on the principle of electric impedance of cells, the real-time cell electronic sensing (RT-CES) system was used to monitor the effect of epirubicin (EPI), cisplatinum (DDP) and carboplatin (CBP) on the growth of HepG2 cells, with the cell index (CI), half maximal inhibitory concentration (IC50) and detachment curve as evaluation indexes. Meanwhile, cell counting kit-8 (CCK-8) and microscopy were applied for verification. The results showed that CI curve could sensitively real-time profile the inhibitory effect of model drugs on HepG2 cells. The IC50 of EPI, DDP and CBP were 0.53 +/- 0.04, 9.79 +/- 0.26 and 597.00 +/- 3.79 microg x mL(-1), respectively. What's more, the significant differences of detachment curves of the three drugs indicated that their functional mechanisms might be different, this is consistent with the literature. The RT-CES system with non-invasive, label-free and real-time characteristics could be used to monitor the bio-response profile of the three drugs to HepG2 cells, allowing to qualitatively and quantitatively distinguish the antitumor activities of the three drugs, and could be a complementary method for the present screening of antitumor compounds.
Antineoplastic Agents ; pharmacology ; Biosensing Techniques ; methods ; Cell Count ; Cell Line, Tumor ; Cisplatin ; pharmacology ; Drug Screening Assays, Antitumor ; Electric Impedance ; Humans