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Lung cancer is one of the most common and lethal types of oncological diseases. Despite the advanced therapeutic approaches, the prognosis for lung cancer still remains poor. Apparently, there is an imperative need for more efficient therapeutic strategies. In this work we report that concurrent treatment of human adenocarcinoma A549 cells with specific concentrations of two antitumor agents, the sphingosine kinase 1 inhibitor N, N dimethylsphingosine (DMS) and the alkylphosphocholine miltefosine, induced synergistic cytotoxic effect, which was confirmed by calculation of the combination index. The simultaneous action of these agents, induced significant decrease of A549 cell number, as well as pronounced morphological alterations. Combined drugs caused substantial apoptotic events, and significant reduction of the pro-survival marker sphingosine- 1-phosphate (S1P), when compared to the individual treatments with each of the anticancer drugs alone. Miltefosine is known to affect the synthesis of choline-containing phospholipids, including sphingomyelin, but we report for the first time that it also reduces S1P. Here we suggest a putative mechanism underlying the effect of miltefosine on sphingosine kinase 1, involving miltefosine-induced inhibition of protein kinase C. In conclusion, our findings provide a possibility for treatment of lung cancer cells with lower concentrations of the two antitumor drugs, DMS and miltefosine, which is favorable, regarding their potential cytotoxicity to normal cells., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Drug loading into nanocarriers is used to facilitate drug delivery to target cells and organs. We have previously reported a change in cellular localization of epirubicin after loading to poly(butyl cyanoacrylate) (PBCA) nanoparticles. We aimed to further investigate the altered cellular localization and cellular responses to the described drug formulation., Materials and Methods: HeLa cells were treated with epirubicin-loaded PBCA nanoparticles prepared by the pre-polymerization method. A systematic study was performed to evaluate the formulation cytotoxicity. Cellular localization and uptake of the formulation as well as cellular response to the treatment were evaluated., Results: Our studies revealed decreased cytotoxicity of the nanoparticle-formulated epirubicin compared to the free drug as well as a noticeable change in the drug's intracellular localization. Epirubicin-loaded nanoparticles were internalized via endocytosis, accumulated inside endosomal vesicles and induced a two-fold stronger pro-apoptotic signal when compared to the free drug. The level of the tumor suppressor protein p53 in HeLa cells increased significantly upon treatment with free epirubicin, but remained relatively unchanged when cells were treated with equivalent dose of nanoparticle-loaded drug, suggesting a possible shift from p53-dependent DNA/RNA intercalation-based induction of cytotoxicity by free epirubicin to a caspase 3-induced cell death by the epirubicin-loaded PBCA formulation.

Investigations were performed on the influence of resveratrol on the lipid composition, metabolism, fatty acid and peroxide level in plasma membranes of hepatocytes, isolated from aged rats. Hepatocytes were chosen due to the central role of the liver in lipid metabolism and homeostasis. The obtained results showed that the level of sphingomyelin (SM) and phosphatidylserine (PS) was augmented in plasma membranes of resveratrol-treated senescent hepatocytes. The saturated/unsaturated fatty acids ratio of the two most abundant membrane phospholipids, phosphatidylcholine (PC) and phosphatidylethanolamine (PE), was decreased as a result of resveratrol treatment. The neutral sphingomyelinase was found to be responsible for the increase of SM and the decrease of ceramide in plasma membranes of resveratrol-treated senescent hepatocytes. Using labeled acetate as a precursor of lipid synthesis we demonstrated, that resveratrol treatment resulted in inhibition mainly of phospholipid synthesis, followed by fatty acids synthesis. Resveratrol induced reduction of specific membrane-associated markers of apoptosis such as localization of PS in the external plasma membrane monolayer and ceramide level. Finally, the content of lipid peroxides was investigated, because the unsaturated fatty acids, which were augmented as a result of resveratrol treatment, are an excellent target of oxidative attack. The results showed that the lipid peroxide level was significantly lower, ROS were slightly reduced and GSH was almost unchanged in resveratrol-treated hepatocytes. We suggest, that one possible biochemical mechanism, underlying the reported resveratrol-induced changes, is the partial inactivation of neutral sphingomyelinase, leading to increase of SM, the latter acting as a native membrane antioxidant. In conclusion, our studies indicate that resveratrol treatment induces beneficial alterations in the phospholipid and fatty acid composition, as well as in the ceramide and peroxide content in plasma membranes of senescent hepatocytes. Thus, the presented results imply that resveratrol could improve the functional activity of the membrane lipids in the aged liver by influencing specific membrane parameters, associated with the aging process., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

This article describes the preparation of epirubicin-loaded nanoparticles, prepared by loading of the drug in pre-polymerized poly(butyl cyanoacrylate) nanoparticles, their physicochemical characterization and in vitro evaluation on human lung adenocarcinoma (A549) cells. Nanoparticles were also coated in aqueous dispersions with two different non-ionic surfactants (Pluronic F68 and Polysorbate 80). All particles were spherical in shape, with monomodal size distributions. The zeta-potentials at pH 7.4 increased with augmentation of the particle drug content. The increased drug content was found to correlate with the initial concentration of the drug, used for the particle preparation. In vitro studies on A549 cells showed that the drug-loaded nanoparticles, as well as the combinations of free drug and empty nanoparticles, exhibited higher cytotoxicity than the free drug alone. The presence of surfactants also resulted in increased cytotoxicity. Fluorescent imaging of epirubicin internalization by the adenocarcinoma cells revealed that the free drug was predominantly localized in the cell nucleus, while a cytoplasmic localization was observed for the nanoparticle-bound drug formulations, suggesting the probability of nanoparticle endocytosis. Thus the hereby presented results could be useful for development of nanoparticle-based anthracycline formulations for treatment of lung adenocarcinoma., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This article describes the preparation, physicochemical characterization and cytotoxicity assessment of novel colloidal formulations of etoposide based on poly(butyl cyanoacrylate) nanoparticles. Nanoparticles were prepared by controlled emulsion polymerization of butyl cyanoacrylate in aqueous medium using two different non-ionic colloidal stabilizers (pluronic F68 and polysorbate 80). The nanoparticles were spherical in shape, with average size ranging from 110-150 nm (empty nanoparticles) to 170-260 nm (drug-loaded nanoparticles), monomodal size distributions, and negative zeta-potentials at pH 7.4. Drug loading efficiency was around 63-68%. More than 80% of the drug was released from the formulations within 6-7h of dialysis experiments. Pluronic-coated nanoparticles possessed lower magnitude of the ζ-potentials (around -4 mV) in comparison with the polysorbate-coated ones (around -12 mV). All tested etoposide formulations induced apoptosis in adenocarcinoma human epithelial (A549) cells, as evident from condensation of chromatin and fragmentation of nuclei. It was found that etoposide formulated with poly(butyl cyanoacrylate) nanoparticles and polysorbate 80 exhibited the highest cytotoxicity toward adenocarcinoma cells., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This report describes the preparation of poly(butyl cyanoacrylate) nanospheres loaded with epirubicin by nanoprecipitation, their characterization and in vitro evaluation of the drug uptake and cytotoxicity on cancer cell lines. The epirubicin-loaded nanospheres were prepared by nanoprecipitation using presynthesized polymer and dextran 40 as a colloidal stabilizer at different pH and initial drug concentrations. The nanospheres were characterized for particle morphology, size distribution, zeta-potential and drug loading. Epirubicin-loaded particles with diameters around 350 nm were obtained. Drug loading depended on the pH and epirubicin concentration. Epirubicin was more cytotoxic when loaded in nanospheres. Drug release was studied by dialysis method. Cytotoxicity and drug uptake experiments were performed on HeLa and A549 cell lines. It was found that addition of polysorbate 80 could increase cytotoxicity. The cytotoxicity was found to correlate with the drug uptake by cells. The findings reported here demonstrate that epirubicin-loaded nanospheres of poly(butyl cyanoacrylate) can be successfully prepared by the nanoprecipitation approach as alternative to the well-known polymerization-based methods. It is found that the epirubicin-loaded nanospheres are more cytotoxic than the free drug to human carcinoma cell lines in vitro. The higher cytotoxicity of the obtained epirubicin formulations, compared with the free drug, is due to enhanced cellular internalization of epirubicin., (Copyright © 2011 Elsevier B.V. All rights reserved.)