Lomustine Incorporated Lipid Nanostructures Demonstrated Preferential Anticancer Properties in C6 Glioma Cell Lines with Enhanced Pharmacokinetic Profile in Mice

Effective treatment of glioma still stands as a challenge in medical science. The work aims for the fabrication and evaluation of lipid based nanostructures for improved delivery of lomustine to brain tumor cells. Experimental formulations (LNLs) were developed by modified lipid layer hydration technique and evaluated for different in vitro characteristics like particle size analysis, surface charge, surface morphology, internal structure, in vitro drug loading, drug release profile etc. Anticancer potential of selected LNLs was tested in vitro on C6 glioma cell line. Electron microscopic study depicted a size of less than 50 nm for the selected LNLs along wirh 8.8% drug loading with a sustained drug release tendency over 48 h study period. Confocal microscopy revealed resonable internalization of the selected LNL in C6 cells. LNLs were found more cytotoxic than free drug and blank nanocarriers as depicted from MTT assay. The selected LNL showed improved pharmacokinetic profile both in blood and brain in the experimental mice models along with negligible hemolysis in mice blood cells. Further studies are warranted for the future translation of LNLs at clinics.

Synergistic Apoptotic Effect of Naringenin on enhancing the Anti-Glioma Efficacy of Temozolomide in an in vitro Experimental Model

Glioma is one of the most devastating and difficult-totreat brain tumors with a very poor prognosis. Despite the current treatment modalities, the overall survival rate is only 5% contributing to a high mortality rate. Nevertheless, of emerging treatment strategies, there is still a rising need for novel mitigation strategies to counteract glioma aggressiveness. One attempt towards this long-term goal was made in this study to reveal the combined efficacy of naringenin, a bioactive flavonoid on enhancing the anti-glioma potency of temozolomide in C6 glioma cells. The cytotoxic effect of temozolomide and naringenin, both individually and in combination was assessed by employing MTT assay. The synergistic effect of the drugs temozolomide and naringenin was determined by calculating the combination index. To confirm the presence of apoptotic changes in the cells at morphological level, acridine orange/ethidium bromide staining was performed. Further, the modulatory effects of the drugs on apoptotic genes, caspase-3 and BCL-2 were evaluated using quantitative real time-PCR. Interestingly, we found that the combinatorial drug treatment was in consensus and effectively inhibited the growth of C6 glioma cells in a dose-dependent manner. Furthermore, this combinatorial drug treatment significantly up-regulated the expression of the proapoptotic gene, caspase-3 and down-regulated the anti-apoptotic gene BCL-2 suggesting a shift of equilibrium towards apoptosis. Our findings suggest that naringenin can be employed as a potent drug to enhance the anti-glioma efficacy of temozolomide and could be therapeutically exploited for the management of glioma.

Antitumoral Action of Resveratrol Through Adenosinergic Signaling in C6 Glioma Cells

Gliomas are the most common and aggressive primary tumors in the central nervous system. The nucleoside adenosine is considered to be one major constituent within the tumor microenvironment. The adenosine level mainly depends on two enzymatic activities: 5′-nucleotidase (5′NT or CD73) that synthesizes adenosine from AMP, and adenosine deaminase (ADA) that converts adenosine into inosine. Adenosine activates specific G-protein coupled receptors named A1, A2A, A2B, and A3 receptors. Resveratrol, a natural polyphenol present in grapes, peanuts, and berries, shows several healthy effects, including protection against cardiovascular, endocrine, and neurodegenerative diseases and cancer. However, the molecular mechanisms of resveratrol actions are not well known. Recently, we demonstrated that resveratrol acts as an agonist for adenosine receptors in rat C6 glioma cells. The present work aimed to investigate the involvement of adenosine metabolism and adenosine receptors in the molecular mechanisms underlying the antitumoral action of resveratrol. Results presented herein show that resveratrol was able to decrease cell numbers and viability and to reduce CD73 and ADA activities, leading to the increase of extracellular adenosine levels. Some resveratrol effects were reduced by the blockade of A1 or A3 receptors by DPCPX or MRS1220, respectively. These results suggest that reduced CD73 activity located in the plasma membrane in addition to a fine-tuned modulatory role of adenosine receptors could be involved, at least in part, in the antiproliferative action of resveratrol in C6 glioma cells.

Intratumoral administration of astatine-211-labeled gold nanoparticle for alpha therapy

Background 211At is a high-energy α-ray emitter with a relatively short half-life and a high cytotoxicity for cancer cells. Its dispersion can be imaged using clinical scanners, and it can be produced in cyclotrons without the use of nuclear fuel material. This study investigated the biodistribution and the antitumor effect of 211At-labeled gold nanoparticles (211At-AuNP) administered intratumorally. Results AuNP with a diameter of 5, 13, 30, or 120 nm that had been modified with poly (ethylene glycol) methyl ether (mPEG) thiol and labeled with 211At (211At-AuNP-S-mPEG) were incubated with tumor cells, or intratumorally administered to C6 glioma or PANC-1 pancreatic cancers subcutaneously transplanted into rodent models. Systemic and intratumoral distributions of the particles in the rodents were then evaluated using scintigraphy and autoradiography, and the changes in tumor volumes were followed for about 40 days. 211At-AuNP-S-mPEG was cytotoxic when it was internalized by the tumor cells. After intratumoral administration, 211At-AuNP-S-mPEG became localized in the tumor and did not spread to systemic organs during a time period equivalent to 6 half-lives of 211At. Tumor growth was strongly suppressed for both C6 and PANC-1 by 211At-AuNP-S-mPEG. In the C6 glioma model, the strongest antitumor effect was observed in the group treated with 211At-AuNP-S-mPEG with a diameter of 5 nm. Conclusions The intratumoral single administration of a simple nanoparticle, 211At-AuNP-S-mPEG, was shown to suppress the growth of tumor tissue strongly in a particle size-dependent manner without radiation exposure to other organs caused by systemic spread of the radionuclide. Graphic Abstract

Study of the Antioxidant Effects of Coffee Phenolic Metabolites on C6 Glioma Cells Exposed to Diesel Exhaust Particles

The contributing role of environmental factors to the development of neurodegenerative diseases has become increasingly evident. Here, we report that exposure of C6 glioma cells to diesel exhaust particles (DEPs), a major constituent of urban air pollution, causes intracellular reactive oxygen species (ROS) production. In this scenario, we suggest employing the possible protective role that coffee phenolic metabolites may have. Coffee is a commonly consumed hot beverage and a major contributor to the dietary intake of (poly) phenols. Taking into account physiological concentrations, we analysed the effects of two different coffee phenolic metabolites mixes consisting of compounds derived from bacterial metabolization reactions or phase II conjugations, as well as caffeic acid. The results showed that these mixes were able to counteract DEP-induced oxidative stress. The cellular components mediating the downregulation of ROS included extracellular signal-regulated kinase 1/2 (ERK1/2), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and uncoupling protein 2 (UCP2). Contrary to coffee phenolic metabolites, the treatment with N-acetylcysteine (NAC), a known antioxidant, was found to be ineffective in preventing the DEP exposure oxidant effect. These results revealed that coffee phenolic metabolites could be promising candidates to protect against some adverse health effects of daily exposure to air pollution.