betadex and Carcinoma--Non-Small-Cell-Lung

Topics: A549 Cells; Administration, Inhalation; Antibiotics, Antineoplastic; Antitubercular Agents; beta-Cyclodextrins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Diarylquinolines; Drug Carriers; Drug Repositioning; Humans; Lung Neoplasms; Models, Molecular

The purpose of this study was to investigate the impact of anticancer drug erlotinib-randomly methylated-

Topics: A549 Cells; Animals; Antineoplastic Agents; beta-Cyclodextrins; Caco-2 Cells; Calorimetry, Differential Scanning; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Liberation; Erlotinib Hydrochloride; Humans; Intestinal Absorption; Lung Neoplasms; Methylation; Mice; Microscopy, Electron, Scanning; Solubility; Treatment Outcome

Resveratrol (RES), a natural polyphenol in fruits, has shown promising anti-cancer properties. Due to its relative low toxicity which limits the adverse effects observed for conventional chemotherapeutics, RES has been proposed as an alternative. However, the therapeutic applications of RES have been limited due to low water solubility, as well as chemical and physical instability. This study investigated enhancing the anti-cancer activity of RES against non-small-cell-lung-cancer (NSCLC) by complexing with sulfobutylether-β-cyclodextrin (CD-RES) and loading onto polymeric nanoparticles (NPs). The physicochemical properties of the CD-RES NPs were then characterized. The CD-RES inclusion complex increased the water solubility of RES by ~66-fold. CD-RES NPs demonstrated very good aerosolization potential with a mass median aerodynamic diameter of 2.20 μm. Cell-based studies demonstrated improved therapeutic efficacy of CD-RES NPs compared to RES. This included enhanced cellular uptake, cytotoxicity, and apoptosis, while retaining antioxidant activity. The 3D spheroid study indicated an intensified anti-cancer effect of CD-RES NPs. Altogether, these findings marked CD-RES NPs as a potential inhalable delivery system of RES for the treatment NSCLC.

Topics: A549 Cells; Administration, Inhalation; beta-Cyclodextrins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Stability; HEK293 Cells; Humans; Lung Neoplasms; Nanoparticles; Particle Size; Resveratrol

Activation of c-Met, a receptor tyrosine kinase, induces radiation therapy resistance in non-small cell lung cancer (NSCLC). The activated residual of c-Met is located in lipid rafts (Duhon et al. Mol Carcinog 49:739-49, 2010). Therefore, we hypothesized that disturbing the integrity of lipid rafts would restrain the activation of the c-Met protein and reverse radiation resistance in NSCLC. In this study, a series of experiments was performed to test this hypothesis.. NSCLC A549 and H1993 cells were incubated with methyl-β-cyclodextrin (MβCD), a lipid raft inhibitor, at different concentrations for 1 h before the cells were X-ray irradiated. The following methods were used: clonogenic (colony-forming) survival assays, flow cytometry (for cell cycle and apoptosis analyses), immunofluorescence microscopy (to show the distribution of proteins in lipid rafts), Western blotting, and biochemical lipid raft isolation (purifying lipid rafts to show the distribution of proteins in lipid rafts).. Our results showed that X-ray irradiation induced the aggregation of lipid rafts in A549 cells, activated c-Met and c-Src, and induced c-Met and c-Src clustering to lipid rafts. More importantly, MβCD suppressed the proliferation of A549 and H1993 cells, and the combination of MβCD and radiation resulted in additive increases in A549 and H1993 cell apoptosis. Destroying the integrity of lipid rafts inhibited the aggregation of c-Met and c-Src to lipid rafts and reduced the expression of phosphorylated c-Met and phosphorylated c-Src in lipid rafts.. X-ray irradiation induced the aggregation of lipid rafts and the clustering of c-Met and c-Src to lipid rafts through both lipid raft-dependent and lipid raft-independent mechanisms. The lipid raft-dependent activation of c-Met and its downstream pathways played an important role in the development of radiation resistance in NSCLC cells mediated by c-Met. Further studies are still required to explore the molecular mechanisms of the activation of c-Met and c-Src in lipid rafts induced by radiation.

Topics: A549 Cells; Apoptosis; beta-Cyclodextrins; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; CSK Tyrosine-Protein Kinase; Humans; Lung Neoplasms; Membrane Microdomains; Phosphorylation; Proto-Oncogene Proteins c-met; Radiation Tolerance; Radiation-Sensitizing Agents; src-Family Kinases

A novel biodegradable amphiphilic copolymer composed of hydroxypropyl-β-cyclodextrin, polylactide, and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, was successfully synthesized. The chemical structures of copolymers were determined by FT-IR, (1)H nuclear magnetic resonance (NMR) spectroscopy, (13)C NMR, (31)P NMR, thermogravimetric analysis ,and differential scanning calorimetry. Doxorubicin (DOX)-loaded copolymer nanoparticles (NPs) were prepared by double emulsion and nanoprecipitation methods. The factors of copolymer composition and fabrication methods, which influence size and encapsulation efficiency (EE) were investigated. Their EE to DOX could reach 90.6% at an available condition. In vitro release behavior of NPs showed a continuous release after a burst release. The antitumor activity of the DOX-loaded NPs against cancer HepG2 and A549 cells was evaluated by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide method. The DOX-loaded copolymer NPs showed comparable anticancer efficacy with the free drug.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Antibiotics, Antineoplastic; beta-Cyclodextrins; Carcinoma, Non-Small-Cell Lung; Cell Survival; Doxorubicin; Drug Carriers; Ethanolamines; Excipients; Hep G2 Cells; Humans; Hydrophobic and Hydrophilic Interactions; Nanoparticles; Polyesters; Polymers; Tumor Cells, Cultured

Lipid raft, a specialized membrane structure enriched with cholesterol and glycosphingolipid, contains molecules that convey environmental stimuli to the intracellular systems. Authors investigated the effects of raft cholesterol depletion on non-small cell lung cancer (NSCLC) cell migration. Incubation of NSCLC cells in media containing lovastatin resulted in inhibition of cell migration by 63.1-83.3%, whereas raft cholesterol depletion with successive treatment using methyl-beta cyclodextrin (MbetaCD) followed by lovastatin further suppressed their migration by 35.0-57.8%. Raft cholesterol depletion partially inhibited EGF-induced phosphorylation of EGFR and FAK, however, no change was observed in other molecules comprising focal adhesion complex. It resulted in disappearance of filopodia, inhibition of EGF-induced pY397 FAK aggregation, and its destabilization. Cholesterol depletion inhibited phosphorylation of Src on Y416 in the detergent-insoluble fraction followed by decreased localization of total and pY397 FAK in the detergent-insoluble fraction. Minimal changes in these molecules were observed in the detergent-soluble fraction and interactions between FAK and other molecules of the focal adhesion complex were not influenced. Immunocytochemical analysis confirmed translocation of Src from the raft into cytoplasm and disappearance of EGF-induced membrane ruffling by raft cholesterol depletion. In cholesterol-depleted cells, EGF-induced phosphorylation of Src, Akt, and p44/42 in the detergent-insoluble fraction were inhibited whereas phosphorylation of GSK-3beta was unaffected. We conclude that raft cholesterol depletion inhibited NSCLC migration through inhibition of phosphorylation of raft associated Src and dislocation of molecules comprising focal adhesion complexes from raft rather than by inhibiting their recruitment to Src and interaction.

Topics: beta-Cyclodextrins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cholesterol; Epidermal Growth Factor; ErbB Receptors; Focal Adhesion Kinase 1; Focal Adhesions; Humans; Lovastatin; Membrane Microdomains; Oncogene Protein pp60(v-src); Phosphorylation; Protein Stability; Protein Transport; Pseudopodia; Receptor Aggregation

Tubulysins are naturally occurring tetrapeptides with potent antiproliferative activity against multiple cancer cell lines. However, they are also highly toxic in animal models. In order to improve the therapeutic index of this class of compounds, a nanoparticle prodrug of tubulysin A (TubA) was synthesized and evaluated in vitro and in vivo.. A thiol derivative of TubA was covalently attached to a linear, beta-cyclodextrin based polymer through a disulfide linker (CDP-TubA). The polymer conjugate assembled into stable nanoparticles. Inhibition of tubulin polymerization and antiproliferative activity of the polymer conjugate were evaluated in vitro. The preclinical efficacy of CDP-TubA administered i.v. was evaluated in nude mice bearing s.c. implanted human HT29 colorectal and H460 non-small cell lung carcinoma tumors.. The IC(50) of CDP-TubA (in Tub A equivalents) was 24, 5, and 10 nmol/L versus 3, 1, and 2 nmol/L for Tub A in NCI-H1299 (lung), HT-29 (colon), and A2780 (ovarian) cell lines, respectively. Tub A and the active thiol derivative were potent inhibitors of tubulin polymerization, whereas CDP-TubA showed minimal inhibition, indicating that target inhibition requires release of the peptide drug from the nanoparticles. The maximum tolerated dose of CDP-TubA was 6 mg/kg (in TubA equivalents) versus 0.05 mg/kg for TubA in nude mice. In vivo, a single treatment cycle of three weekly doses of CDP-TubA showed a potent antitumor effect and significantly prolonged survival compared with TubA alone.. Cyclodextrin polymerized nanoparticles are an enabling technology for the safe and effective delivery of tubulysins for the treatment of cancer.

Topics: Animals; beta-Cyclodextrins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Evaluation, Preclinical; HT29 Cells; Humans; Inhibitory Concentration 50; Lung Neoplasms; Maximum Tolerated Dose; Mice; Mice, Nude; Nanoparticles; Oligopeptides; Polymers; Prodrugs; Solubility; Tubulin; Xenograft Model Antitumor Assays