C6 Cancer Cell Research Articles

MELATONIN ENHANCES TEMOZOLOMIDE-INDUCED APOPTOSIS IN GLIOBLASTOMA AND NEUROBLASTOMA CELLS.

The combination of temozolomide (TMZ) and paclitaxel (PTX) is the most commonly used chemotherapy regimen for glioblastoma, but there is no specific treatment for neuroblastoma due to the acquired multidrug resistance. Approximately half of treated glioblastoma patients develop resistance to TMZ and experience serious side effects. Melatonin (MEL), a multifunctional hormone long known for its antitumor effects, has a great advantage in combination cancer therapy thanks to its ability to affect tumors differently than normal cells. This study aims to evaluate the in vitro inhibitory effects of MEL in combination with TMZ on cancer cell viability and to elucidate the underlying mechanisms in the glioblastoma and neuroblastoma cell lines. C6 (Rattus norvegicus) and N1E-115 (Mus musculus) cancer cell lines and C8-D1A (mice) healthy cell lines were used. Cell proliferation was evaluated using the MTT test. IC50 values were determined by probit analysis. Two concentrations of TMZ (IC50 and 1/2 IC50) were used to induce cytotoxicity in the C6 and N1E-115 cell lines, both alone and in combination with PXT and MEL (all at IC50). The viable, dead, and apoptotic cells were determined by image-based cytometry using Annexin V/PI staining. The gene expression related to signaling pathways was assessed by the quantitative reverse transcription polymerase chain reaction (qRT-PCR), and key proteins were identified by the Western blot analysis. MTT assay showed that the combination of TMZ and MEL significantly reduces the viability of both glioblastoma and neuroblastoma cells compared to the vehicle-treated controls. Notably, MEL combined with 1/2 IC50 TMZ showed a significant death rate of cancer cells compared to controls and PTX. According to qRT-PCR data, the TMZ + MEL combination resulted in the upregulation of the genes of antioxidative enzymes (Sod1 and Sod2) and DNA repair genes (Mlh1, Exo1, and Rad18) in both cell lines. Moreover, the levels of Nfkb1 and Pik3cg were significantly reduced following the TMZ + MEL treatment. The combination of MEL with TMZ also enhanced the cell cycle arrest and increased the expression of p53 and pro-apoptotic proteins (Bax and caspase-3), while significantly decreasing the expression of anti-apoptotic protein Bcl-2. Our findings indicate that the combination of MEL with a low dose of TMZ may serve as an upstream inducer of apoptosis. This suggests the potential development of a novel selective therapeutic strategy as an alternative to TMZ for the treatment of both glioblastoma and neuroblastoma.

Comprehensive phenolic profiling and biological evaluation of Centaurea glastifolia L. (Asteraceae)

The present investigation focused on the comprehensive analysis of the phenolic profile of Centaurea glastifolia L. (Asteraceae) and the assessment of its diverse biological activities. Utilising LC-MS/MS, the phytochemical composition of the 70% methanol extract of Centaurea glastifolia (CG-ME) was thoroughly elucidated, revealing the presence of 30 distinct phytochemical compounds. Notably, major phenolic constituents identified in the extract included quinic acid, chlorogenic acid, luteolin-7-O-glucoside, kaempferol-3-O-glucoside, luteolin, and apigenin-7-O-glucoside. The antioxidant, antibacterial, antiproliferative, and cytotoxic activities of CG-ME were investigated. The CG-ME exhibited a moderate capacity for scavenging DPPH radicals (IC50: 50.05 ± 1.58 µg/mL) and FRAP (63.96 ± 0.39 mg TE/g extract), indicating a moderate level of antioxidant activity. Moreover, CG-ME demonstrated significant antiproliferative effects (GI50: 1.10 and 1.30 µg/mL) on cancer cells (C6 and HTC cancer cell lines, respectively) while displaying low cytotoxicity towards normal cells (LC50: >1000 µg/mL). In terms of antibacterial activity, CG-ME was found to be inactive against tested both Gram-positive and Gram-negative bacterial strains (MIC > 500 µg/mL). The extracts had a promising antiproliferative effect on C6, HeLa, and HT29 cancer cell lines with a less cytotoxic effect (10.5–14.2%) against normal cells.

Matrix Protein of Vesicular Stomatitis Virus Targets the Mitochondria, Reprograms Glucose Metabolism, and Sensitizes to 2-Deoxyglucose in Glioblastoma.

A potential therapeutic approach for cancer treatment is target oxidative phosphorylation and glycolysis simultaneously. The matrix protein of vesicular stomatitis virus (VSV MP) can target the surface of mitochondria, causing morphological changes that may be associated with mitochondrial dysfunction and oxidative phosphorylation inhibition. Previous research has shown that mitochondrial abnormalities can direct glucose metabolism toward glycolysis. Thus, after treatment with VSV MP, glycolysis inhibition is necessary to completely block glucose metabolism and eradicate cancer. Here, to inhibit glycolysis, the 2-deoxy-D-glucose (2-DG), a synthetic glucose analog was used to combine with VSV MP to treat cancer. This study aims to determine how VSV MP affects the glucose bioenergetic metabolism of cancer cells and to evaluate the synergistic effect of 2-DG when combined with VSV. Our results indicated that in U87 and C6 glioblastoma cell lines, VSV MP caused mitochondrial membrane potential loss, cytochrome c release, and glucose bioenergetics metabolism reprogramming. When combined with 2-DG, VSV MP synergistically aggravated cell viability, apoptosis, and G2/M phase arrest. Meanwhile, the combination therapy exacerbated ATP depletion, activated AMPK, and inhibited mammalian target of rapamycin signaling pathways. In addition, 2-DG treatment alone induced autophagy in glioblastoma cells; however, VSV MP inhibited the autophagy induced by 2-DG in combined treatment and finally contributed to the enhanced cytotoxic effect of the combination strategy in U87 and C6 cancer cells. In the orthotopic U87 glioblastoma model and subcutaneous C6 glioblastoma model, the combined treatment led to significant tumor regression and prolonged survival. A potent therapeutic approach for treating glioblastoma may be found in the combination of VSV MP and glycolytic inhibitors.

Toxicity of Large and Small Surface-Engineered Upconverting Nanoparticles for In Vitro and In Vivo Bioapplications.

In this study, spherical or hexagonal NaYF4:Yb,Er nanoparticles (UCNPs) with sizes of 25 nm (S-UCNPs) and 120 nm (L-UCNPs) were synthesized by high-temperature coprecipitation and subsequently modified with three kinds of polymers. These included poly(ethylene glycol) (PEG) and poly(N,N-dimethylacrylamide-co-2-aminoethylacrylamide) [P(DMA-AEA)] terminated with an alendronate anchoring group, and poly(methyl vinyl ether-co-maleic acid) (PMVEMA). The internalization of nanoparticles by rat mesenchymal stem cells (rMSCs) and C6 cancer cells (rat glial tumor cell line) was visualized by electron microscopy and the cytotoxicity of the UCNPs and their leaches was measured by the real-time proliferation assay. The comet assay was used to determine the oxidative damage of the UCNPs. An in vivo study on mice determined the elimination route and potential accumulation of UCNPs in the body. The results showed that the L- and S-UCNPs were internalized into cells in the lumen of endosomes. The proliferation assay revealed that the L-UCNPs were less toxic than S-UCNPs. The viability of rMSCs incubated with particles decreased in the order S-UCNP@Ale-(PDMA-AEA) > S-UCNP@Ale-PEG > S-UCNPs > S-UCNP@PMVEMA. Similar results were obtained in C6 cells. The oxidative damage measured by the comet assay showed that neat L-UCNPs caused more oxidative damage to rMSCs than all coated UCNPs while no difference was observed in C6 cells. An in vivo study indicated that L-UCNPs were eliminated from the body via the hepatobiliary route; L-UCNP@Ale-PEG particles were almost eliminated from the liver 96 h after intravenous application. Pilot fluorescence imaging confirmed the limited in vivo detection capabilities of the nanoparticles.

Liquid chromatography-tandem mass spectrometry profile and antioxidant, antimicrobial, antiproliferative, and enzyme activities of Thymus pectinatus and Thymus convolutus: in vitro and in silico approach.

The objective of this study is to investigate the antiproliferative, antioxidant, antimicrobial, and enzyme activity capacities and phytochemical compositions of Thymus pectinatus (TP), Thymus convolutus (TC), which are endemic to Türkiye. Quantitative analysis of phenolic compounds in the extracts was conducted using liquid chromatography-tandem mass spectrometry, targeting 53 phenolic compounds. Rosmarinic acid, quinic acid, and cynaroside were identified as the major compounds, exhibiting quantitative variation in both extracts. The extracts had a high total phenolic content, with 113.57 ± 0.58 mg gallic acid equivalents (GAE)/g extract for TP and 130.52 ± 1.05 mg GAE/g extract for TC. Furthermore, although both extracts exhibited high total flavonoid content; the TP extract (75.12 ± 1.65 mg quercitin equivalents (QE)/g extract) displayed a higher flavonoid content than the TC extract (30.24 ± 0.74 mg QE/g extract) did. The extracts had a promising antiproliferative effect on C6, HeLa, and HT29 cancer cell lines with a less cytotoxic effect (10.5-14.2%) against normal cells. Both extracts exhibited very potent inhibitory activity against the xanthine oxidase enzyme, with half-maximal inhibitory concentration values of respectively 2.07 ± 0.03 μg mL-1 and 2.76 ± 0.06 μg mL-1 and moderate activity against tyrosinase and α-glucosidase. Docking simulations proved that rosmarinic acid and cynaroside, the major components of the extracts, were the most potent inhibitors of xanthine oxidase. According to antimicrobial activity results, the TC extract exhibited moderate activity against Staphylococcus aureus, and the TP extract had strong activity against both Enterococcus faecium and S. aureus. These findings emphasize the beneficial effects of the two endemic Thymus species on human health and suggest their potential use as plant-derived bioactive agents. © 2024 Society of Chemical Industry.

R-ketorolac ameliorates cancer-associated cachexia and prolongs survival of tumour-bearing mice.

Cancer-associated cachexia (CAC) is a debilitating syndrome associated with poor quality of life and reduced life expectancy of cancer patients. CAC is characterized by unintended body weight reduction due to muscle and adipose tissue loss. A major hallmark of CAC is systemic inflammation. Several non-steroidal anti-inflammatory drugs (NSAIDs) have been suggested for CAC treatment, yet no single medication has proven reliable. R-ketorolac (RK) is the R-enantiomer of a commonly used NSAID. The effect of RK on CAC has not yet been evaluated. Ten- to 11-week-old mice were inoculated with C26 or CHX207 cancer cells or vehicle control (phosphate-buffered saline [PBS]). After cachexia onset, 2mg/kg RK or PBS was administered daily by oral gavage. Body weight, food intake and tumour size were continuously measured. At study endpoints, blood was drawn, mice were sacrificed and tissues were excised. Immune cell abundance was analysed using a Cytek® Aurora spectral flow cytometer. Cyclooxygenase (COX) activity was determined in lung homogenates using a fluorometric kit. Muscle tissues were analysed for mRNA and protein expression by quantitative real-time PCR and western blotting analysis, respectively. Muscle fibre size was determined on histological slides after haematoxylin/eosin staining. Ten-day survival rate of C26-bearing animals was 10% while RK treatment resulted in a 100% survival rate (P=0.0009). Chemotherapy resulted in a 10% survival rate 14days after treatment initiation, but all mice survived upon co-medication with RK and cyclophosphamide (P=0.0001). Increased survival was associated with a protection from body weight loss in C26 (-0.61±1.82 vs. -4.48±2.0g, P=0.0004) and CHX207 (-0.49±0.33 vs. -2.49±0.93g, P=0.0003) tumour-bearing mice treated with RK, compared with untreated mice. RK ameliorated musculus quadriceps (-1.7±7.1% vs. -27.8±8.3%, P=0.0007) and gonadal white adipose tissue (-18.8±49% vs. -69±15.6%, P=0.094) loss in tumour-bearing mice, compared with untreated mice. Mechanistically, RK reduced circulating interleukin-6 (IL-6) concentrations from 334±151 to 164±123pg/mL (P=0.047) in C26 and from 93±39 to 35±6pg/mL (P=0.0053) in CHX207 tumour-bearing mice. Moreover, RK protected mice from cancer-induced T-lymphopenia (+1.8±42% vs. -49.2±12.1% in treated vs. untreated mice, respectively). RK was ineffective in ameliorating CAC in thymus-deficient nude mice, indicating that the beneficial effect of RK depends on T-cells. RK improved T-lymphopenia and decreased systemic IL-6 concentrations, resulting in alleviation of cachexia and increased survival of cachexigenic tumour-bearing mice, even under chemotherapy and independent of COX inhibition. Considering its potential, we propose that the use of RK should be investigated in patients suffering from CAC.

In vitro study: green synthesis and evaluation of MgO/C-dots/DOX phosphorescent nanocomposites for photodynamic/photocatalytic therapy of tumors

MgO nanoparticles (NPs) and carbon dots (C-dots) were synthesized by co-precipitation and hydrothermal techniques. In the next step, as-synthesized NPs were modified by C-dots. Then, polyethylene glycol (PEG) was conjugated with MgO/Cdots. Finally, Doxorubicin (Dox) as an anticancer drug was loaded on MgO/Cdots/PEG nanocomposites. The XRD pattern showed the characteristic peaks of C-dots and MgO. The FTIR spectrum showed that MgO/C-dots possessed the carboxyl functional groups, allowing DOX to be loaded onto MgO/C-dots/PEG through hydrogen bonds. The particle size of MgO, C-dots, MgO/C-dots, and MgO/C-dots/PEG/DOX was 20–30, 5–10, 30–40, and 100–130 nm, respectively, using TEM, DLS, and FESEM techniques. MgO, MgO/C-dots, and MgO/C-dots/DOX were fluorescent NPs when excited by a UV source. Anthracene and methylene blue were used as fluorescent probes to identify the reactive oxygen species (ROS) produced by UV excitation. The activity of MgO/C-dots and MgO/C-dots/DOX against colorectal cancer (C26) cells, after repeated 5-min illumination with both UV-light and red light LEDs, were measured by MTT assay. C26 cancer cells incubated with DOX-loaded MgO/C-dots and exposed to either wavelength (UV and red) killed ∼70% of cells. The green synthesized nanocomposites could act as anti-cancer photosensitizers probably by a photocatalytic mechanism.

Chlorin e6-modified iron oxide nanoparticles for photothermal-photodynamic ablation of glioblastoma cells.

Introduction: The effective treatment of glioblastoma still remains a great challenge. We herein report the development of chlorin e6 (Ce6)-conjugated iron oxide (Fe3O4-Ce6) nanoparticles for ablation of glioblastoma cells via combining photothermal therapy (PTT) with photodynamic therapy (PDT). Methods: Ce6 was conjugated to the synthesized Fe3O4 nanoparticles to form Fe3O4-Ce6 nanoparticles displaying the optical property of Ce6. Results and discussion: Under 808nm laser irradiation, Fe3O4-Ce6 nanoparticles generated heat and the temperature increase did not have obvious changes after five cycles of laser irradiation, suggesting their good photothermal effect and photothermal stability. In addition, 660nm laser irradiation of Fe3O4-Ce6 nanoparticles produced singlet oxygen (1O2) to mediate PDT. The Fe3O4-Ce6 nanoparticles without laser irradiation showed a low cytotoxicity, but they would obviously kill C6 cancer cells after laser irradiation via the combinational effect of PTT and PDT. Fe3O4-Ce6 nanoparticles thus could be used as a nanotherapeutic agent for combinational ablation of glioblastoma cells.

Proteomic analysis of the small extracellular vesicles and soluble secretory proteins from cachexia inducing and non-inducing cancer cells.

Cancer cachexia is a wasting syndrome characterised by the loss of fat and/or muscle mass in advanced cancer patients. It has been well-established that cancer cells themselves can induce cachexia via the release of several pro-cachectic and pro-inflammatory factors. However, it is unclear how this process is regulated and the key cachexins that are involved. In this study, we validated C26 and EL4 as cachexic and non-cachexic cell models, respectively. Treatment of adipocytes and myotubes with C26 conditioned medium induced lipolysis and atrophy, respectively. We profiled soluble secreted proteins (secretome) as well as small extracellular vesicles (sEVs) released from cachexia-inducing (C26) and non-inducing (EL4) cancer cells by label-free quantitative proteomics. A total of 1268 and 1022 proteins were identified in the secretome of C26 and EL4, respectively. Furthermore, proteomic analysis of sEVs derived from C26 and EL4 cancer cells revealed a distinct difference in the protein cargo. Functional enrichment analysis using FunRich highlighted the enrichment of proteins that are implicated in biological processes such as muscle atrophy, lipolysis, and inflammation in both the secretome and sEVs derived from C26 cancer cells. Overall, our characterisation of the proteomic profiles of the secretory factors and sEVs from cachexia-inducing and non-inducing cancer cells provides insights into tumour factors that promote weight loss by mediating protein and lipid loss in various organs and tissues. Further investigation of these proteins may assist in highlighting potential therapeutic targets and biomarkers of cancer cachexia.

Aptamer-functionalized mesenchymal stem cells-derived exosomes for targeted delivery of SN38 to colon cancer cells.

Known as natural nanovesicles, exosomes have attracted increased attention as biocompatible carriers throughout recent years, which can provide appropriate sources for incorporating and transferring drugs to desired cells in order to improve their effectiveness and safety. This study implicates the isolation of mesenchymal stem cells from adipocyte tissue (ADSCs) to acquire a proper amount of exosomes for drug delivery. As the exosomes were separated by ultracentrifugation, SN38 was entrapped into ADSCs-derived exosomes through the combination method of incubation, freeze-thaw, and surfactant treatment (SN38/Exo). Then, SN38/Exo was conjugated with anti-MUC1 aptamer (SN38/Exo-Apt), and its targeting ability and cytotoxicity towards cancer cells were investigated. Encapsulation efficiency of SN38 into exosomes (58%) was significantly increased using our novel combination method. Furthermore, the in vitro results were indicative of the great cellular uptake of SN38/Exo-Apt and its significant cytotoxicity on Mucin 1 overexpressing cells (C26 cancer cells) without noticeable cytotoxicity on normal cells (CHO cells). The results propose that our approach developed an efficient method for loading SN38 as a hydrophobic drug into exosomes and decorating them with MUC1 aptamer against Mucin 1 overexpressing cells. So, SN38/Exo-Apt could be considered a great platform in the future for the therapy of colorectal cancer.

Fabrication of Etoposide-loaded superparamagnetic iron oxide nanoparticles (SPIONs) induced apoptosis in glioma cancer cells

Recent research has shown that etoposide (ETP), an immunomodulatory medication, can have cytotoxic effects. When accompanied by nano-drug delivery, this possibility can lead to a more effective treatment for cancer. This study involved the delivery of ETP via PDA@SPIONs (termed as ETP-PDA@SPIONs), which are superparamagnetic iron oxide nanoparticles (SPIONs) that have been coated with polydopamine (PDA) and utilized to treat C6 and U87 glioma cancer cell lines. The particle diameter, polydispersive index (PDI), zeta potential, and shape of nanoparticles were determined. The fabricated nanoparticles had a mean particle size of 164 ± 7 nm and a − 37 ± 3 mv zeta potential. Cell lines were tested for sensitivity to PDA@SPIONs, free-ETP, and ETP-PDA@SPIONs. On the cell lines, we tested the proliferation of PDA@SPIONs, free-ETP, and PDA@SPIONs loaded with ETP. The cytotoxicity of ETP-PDA@SPIONs was substantially higher than that of free-ETP-treated cells. The cells' morphological changes were examined by dual staining (acridine orange/ethidium bromide, AO/EB) and nuclear staining methods. Interestingly, this inhibitory impact was not ascribed to the known cellular membrane destruction, cell membrane damage, and reactive oxygen species (ROS). Further tests demonstrated that the nanoparticles substantially impacted mitochondrial functioning, resulting in an aberrant mitochondrial shape, and reduced mitochondrial membrane potential (MMP). Future studies into glioma cancer therapy may want to investigate using the proposed ETP-loaded nanoparticles.

Multifunctional BODIPY embedded non-woven fabric for CO release and singlet oxygen generation.

Materials that can simultaneously release CO and generate singlet oxygen upon visible light irradiation under ambient conditions are highly desirable for therapeutic applications. Furthermore, materials that can sequester the undesirable side products into the matrix without affecting the release of CO and singlet oxygen generation would allow them to be used for practical applications. Focussing on these aspects, we prepared two dipicolylamine appended BODIPY‑manganese(I) tricarbonyl complexes wherein the metal core was systematically tethered at 5- and 8- positions of the BODIPY core. The complexes were embedded into a polymer matrix via electrospinning and the resulting non-woven fabrics showed CO release as well as singlet oxygen generation upon irradiation. While the hybrid materials were non-toxic in dark, they were strongly photocytotoxic to c6 cancer cells when exposed to light. Rapid CO release alongside significant singlet oxygen generation, indefinite dark stability, good biocompatibility and negligible dark toxicity makes these fabrics a potent candidate for phototherapeutic applications.

Preparation of C6 cell membrane-coated doxorubicin conjugated manganese dioxide nanoparticles and its targeted therapy application in glioma

In this study, we prepared a C6 cell membrane-coated doxorubicin conjugated manganese dioxide biomimetic nanomedicine system (MnO2-DOX-C6) for the treatment of glioma. In the glioma microenvironment, manganese dioxide could alleviate tumor hypoxia by promoting the decomposition of hydrogen peroxide (H2O2) to generate oxygen and, through a Fenton-like reaction, increase ROS levels in tumor cells, thus inducing oxidative stress to further kill cancer cells. Doxorubicin and manganese dioxide were connected through a hydrazone bond so that doxorubicin could be released only in the acidic environment of the tumor, which helped to reduce the toxicity and side effects of doxorubicin. Encapsulation of glioma C6 cancer cell membrane in MnO2-DOX-C6 made MnO2-DOX possess the homologous targeting ability and also regulated drug release rate. In vitro release experiments showed that the cumulative release of doxorubicin from MnO2-DOX-C6 at a pH of 5.0 for 48 h was 66.84 ± 3.81%, proving that it had pH sensitivity and a sustained-release effect. Cellular uptake experiments showed that MnO2-DOX-C6 had a good ability to target syngeneic tumor cells. MTT, flow cytometry, Western blot, cell immunofluorescence staining and in vivo antitumor experiments demonstrated that MnO2-DOX-C6 could promote C6 cell apoptosis and inhibit its proliferative ability. These results clearly suggested that MnO2-DOX-C6 may be a promising bionic nanosystem agent for the treatment of glioma.

Synthesis and investigation of antiproliferative activity of Ru-NHC complexes against C6 and HeLa cancer cells.

The 2-methylpyridine, 2-diethylaminoethyl, and isopentyl linked a series of symmetric and unsymmetric benzimidazolium salts 2a-e were prepared and used in the synthesis of silver-N-heterocyclic carbene (NHC) complexes (3a-e). The Ru(II)-NHC complexes (4a-h) were synthesized via transmetalation reaction from 3a-e. 4a-h complexes were converted to Ru(II)-NHC.HCl complexes (5ah) by HCl solution of diethyl ether and characterized by different spectroscopic techniques such as 1H and 13C NMR, LC/MS-Q-TOF, FT-IR, elemental analysis, and melting point detection. We examined the effect of the structural difference of complexes on anticancer activity via different arenes and metal centers. Antiproliferative activity of 5a-h and 3a was tested against human cervix adenocarcinoma (HeLa) and rat glioblastoma (C6) cell lines by ELISA assay. The IC50 value of 5b, 5c and 5e complexes exhibited good cytotoxic activity than cisplatin on C6 (14.2 ± 0.5 mM; 16.2 ± 0.4 mM; 24.2 ± 0.7 mM, respectively) and HeLa (11.1 ± 0.5 mM; 13.7 ± 0.3 mM; 22.8 ± 0.8 mM, respectively) cell lines.

Synthesis of New 1-Aryl-2-(3,5-dimethylpyrazol-1-yl)ethanone Oxime Ether Derivatives and Investigation of Their Cytotoxic Effects

In this study, 12 new 1-aryl-2-(3,5-dimethylpyrazol-1-yl)ethanone oxime ether derivatives were designed and synthesized to investigate their cytotoxic effects. The in vitro cytotoxic activities of the compounds were evaluated against cervix, colon, breast, glioma, neuroblastoma, and lung cancer cell lines, as well as a healthy cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazo-lium bromide (MTT) assays with 5-fluorouracil (5-FU) as the reference compound. Compound 5f (IC50 = 5.13 µM) was found to be more effective than 5-FU (IC50 = 8.34 µM) in the C6 cancer cell line, and it had no cytotoxic effect on the L929 healthy cell line. Flow cytometry was used to investigate the mechanism of action of compound 5f on the cell cycle of the C6 cell line. The analysis showed that cell death was significantly due to apoptosis. These results indicate that compound 5f induces cell cycle arrest, and may be effective in treating glioma.

Novel imidazo[2,1-b]thiazole-based anticancer agents as potential focal adhesion kinase inhibitors: Synthesis, in silico and in vitro evaluation.

The purpose of this study was to synthesize imidazo[2,1-b]thiazole derivatives, characterize them with spectroscopical techniques and investigate for cytotoxic and apoptotic effects on glioma C6 cancer cell line. The in vitro anticancer activities were also investigated against focal adhesion kinase. Most of the compounds, particularly the derivatives carrying 3-oxo-1-tiya-4-azaspiro[4.5]decane moiety, exhibited higher or comparable activities in comparison with the reference drug, cisplatin. Compounds with methyl, propyl, phenyl moieties at the eighth and second position of the spirothiazolidinone ring showed high FAK inhibitory activities. In addition, molecular docking studies shed light on the binding modes of the synthesized compounds. The critical interactions with amino acid residues located in the active site were revealed. The results obtained from both biological assay data and computational results might provide insight into developing new inhibitors against focal adhesion kinase.

Carrier-free highly drug-loaded biomimetic nanosuspensions encapsulated by cancer cell membrane based on homology and active targeting for the treatment of glioma

Nanosuspensions, as a new drug delivery system for insoluble drugs, are only composed of a drug and a small amount of stabilizer, which is dispersed in an aqueous solution with high drug-loading, small particle size, high dispersion, and large specific surface area. It can significantly improve the dissolution, bioavailability, and efficacy of insoluble drugs. In this study, paclitaxel nanosuspensions ((PTX)NS) were prepared by an ultrasonic precipitation method, with the characteristics of simple preparation and easy repetition. With the help of a homologous targeting mechanism, a kind of glioma C6 cancer cell membrane (CCM)-coated (PTX)NS was developed and modified with DWSW peptide to obtain DWSW-CCM-(PTX)NS with the functions of BBB penetration and tumor targeting. The results showed that the cancer cell membrane could effectively camouflage the nanosuspensions so that it was not cleared by the immune system and could cross the blood-brain-barrier (BBB) and selectively target tumor tissues. Cell uptake experiments and in vivo imaging confirmed that the uptake of DWSW-CCM-(PTX)NS by tumor cells and the distribution in intracranial gliomas increased. Cytotoxicity test and in vivo anti-glioma studies showed that DWSW-CCM-(PTX)NS could significantly inhibit the growth of glioma cells and significantly prolong the survival time of glioma-bearing mice. Finally, the cancer cell membrane coating endowed the nanosuspensions with the biological properties of homologous adhesion and immune escape. This study provides an integrated solution for improving the targeting of nanosuspensions and demonstrates the encouraging potential of biomimetic nanosuspensions applicable to tumor therapy.

Ligand-modified homologous targeted cancer cell membrane biomimetic nanostructured lipid carriers for glioma therapy

The main treatment measure currently used for glioma treatment is chemotherapy; the biological barrier of solid tumors hinders the deep penetration of nanomedicines and limits anticancer therapy. Furthermore, the poor solubility of many chemotherapeutic drugs limits the efficacy of antitumor drugs. Therefore, improving the solubility of chemotherapeutic agents and drug delivery to tumor tissues through the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB) are major challenges in glioma treatment. Nanostructured lipid carriers (NLCs) have high drug loading capacity, high stability, and high in vivo safety; moreover, they can effectively improve the solubility of insoluble drugs. Therefore, in this study, we used solvent volatilization and ultrasonic melting methods to prepare dihydroartemisinin nanostructured lipid carrier (DHA-NLC). We further used the glioma C6 cancer cell (CC) membrane to encapsulate DHA-NLC owing to the homologous targeting mechanism of the CC membrane; however, the targeting ability of the CC membrane was weak. We accordingly used targeting ligands for modification, and developed a bionanostructured lipid carrier with BBB and BBTB penetration and tumor targeting abilities. The results showed that DHA-loaded NGR/CCNLC (asparagine–glycine–arginine, NGR) was highly targeted, could penetrate the BBB and BBTB, and showed good anti-tumor effects both in vitro and in vivo, which could effectively prolong the survival time of tumor-bearing mice. Thus, the use of DHA-loaded NGR/CCNLC is an effective strategy for glioma treatment and has the potential to treat glioma.

First determination of anticancer, cytotoxic, and in silico ADME evaluation of secondary metabolites of endemic Astragalus leucothrix Freyn & Bornm.

Isolation and characterization of anticancer activity guided secondary metabolites of endemic Astragalus leucothrix Freyn& Bornm were aimed. Aerial parts of the plant were extracted by maceration method in the solvent system methanol-chloroform (1 : 1) at room temperature. The obtained crude extract was dissolved in purified water. Then, the extract was partitioned with n-hexane, chloroform, ethyl acetate, and n-butanol, respectively. Anticancer activity tests of all the fractions were performed against HeLa and C6 cancer cells. The chloroform fraction that has highest anticancer activity was subjected to chromatographic methods such as column chromatography and thin layer chromatography. Pentyl tetratetracontanoate (1), alfalone (2), 3,6,8-tribromoquinoline (3), and 3,6,8-tribromochromenium (4) molecules were detected from this plant for the first time. The structure determinations of the isolated molecules were elucidated by methods such as 1D and 2D NMR, HPLC - TOF / MS, and GC - MS analysis. Finally, anticancer and cytotoxic activity tests of the compounds were performed. Literature review showed that 3,6,8-tribromochromenium is a new compound. IC50 values of compound 1-2 and compound 3-4 mix were determined to be 4.50 ± 0.10, 2.81 ± 0.00, 4.33 ± 0.00 μM against C6 cell, respectively. The drug likeness properties of 1-4 were obtained by SwissADME. According to Lipinski's rule of five; 2-4 could be a new potential anticancer agent.

Novel P,C-orthopalladated complexes containing histidine and phenylalanine amino acids: synthesis, DNA and BSA interactions, in vitro antitumoral activity and molecular docking approach

Novel [Pd(o-CH2C6H4P(o-tolyl)2)(histidine)] (1) and [Pd(o-CH2C6H4P(o tolyl)2)(phenylalanine)] (2) P,C-orthopalladated complexes have been prepared and characterized by elemental analysis, IR and NMR spectroscopy. To study the stability of the compounds in biological media, the complexes were incubated in Tris buffer during 10 days. The absorbance of the compounds remained constant, which confirmed the stability of the complexes in biological media. UV-Vis absorption spectrophotometry, fluorescence spectroscopy and viscosity studies were used to investigate the binding of the complexes with native calf thymus DNA (CT-DNA). These methods along with competitive binding of methylene blue (MB) DNA show that the complexes interact with DNA via groove mode. The UV-Vis absorption spectrophotometry of BSA with complexes has shown an α-helix perturbation induced by a particular interaction between the metal complexes and BSA. In addition, the fluorescence quenching mechanism of BSA with the complexes is a static process, according to the fluorescence spectrometry of bovine serum albumin (BSA). The experimental results of site competitive replacement with specific site markers are clear indications that the complexes bind to site I of BSA. Furthermore, both complexes showed significant selective cytotoxic activity against melanoma B16F0 and colon carcinoma C26 cancer cells as well as normal fibroblast NIH cell line. Ultimately, the binding of Pd(II) complexes to DNA and BSA was verified by molecular docking experiment. Communicated by Ramaswamy H. Sarma