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Vitamin E succinate has gained substantial attention as a potential therapeutic agent for cancer treatment due to its biomedical activities. One of the prominent methods of synthesizing vitamin E succinate is through enzymatic processes, which, although advantageous, presents inherent challenges related to optimization, scalability, and particularly, the poor stability of lipases in organic solvents. Our study addresses these challenges by conducting a comprehensive comparative analysis between Lipase UM1 and three other immobilized commercial lipases, demonstrating Lipase UM1's enhanced resistance to organic solvents and its superior efficiency in vitamin E succinate production. Further optimization experiments with Lipase UM1 led to an unprecedented conversion of 99%. Additionally, we scaled the reaction to a proof‐of‐concept industrial level. The synthesized product was verified using Fourier transform infrared spectroscopy and nuclear magnetic resonance analysis, ensuring its quality and consistency. This study validates Lipase UM1 as an efficient catalyst for vitamin E succinate synthesis, offering a promising avenue for industrial production with potential applications in cancer therapy and beyond. [ABSTRACT FROM AUTHOR]

BACKGROUND: The relative low stability, reusability and activity of enzymes made the industrial production of vitamin E succinate (VES) can only be performed with complex processes and high cost using chemical methods. To address these issues, in the present study, an ionic liquids (ILs) modification strategy was developed to improve the activity and stability of lipases in VES synthesis. RESULTS: The results showed that the [1-butyl-3-methyl imidazole] [N-acetyl-L-proline] ILs modified Candida rugosa lipase (CRL) has the highest modification degree (48.28%), activity (774 U g-1), thermostability and solvent tolerance in three selected modifiers. Additionally, after reaction condition optimization, the highest yield of VES can be improved to 95.18% at 45 °C for 15 h, which was significantly improved compared to some previous studies. CONCLUSION: In the present study, a high-efficiency VES synthesis strategy was successfully developed via modification of lipase. Moreover, the mechanism by which ILs modification can enhance the activity and stability of lipase was investigated via both experimental and computational-aided methods. Molecular dynamics simulation suggested that ILs modification changed the geometry of Phe344 from flat to upright, which significantly reshaped and enhanced the size of substrate binding pocket of CRL. It is also agreement with our circular dichroism and fluorescence spectroscopy results, which suggested that the modification changed the secondary structure of CRL to a certain extent. The larger pocket also endowed the suitable binding pose of succinate, which made the hydrogen bonds between succinate and active site Ser209 become stronger, and thus improving the yield of VES. [ABSTRACT FROM AUTHOR]

In this study, a hybrid conjugate of formononetin (FMN) and vitamin E (VESylated‐FMN) was synthesized through succinic acid linker and investigated for its synergistic effect in diabetes. The conjugate was characterized through Ultra Performance Liquid Chromatography – Mass Spectrometry (UPLC‐MS), High‐Resolution Mass Spectrometry (HRMS), Nuclear Magnetic Resonance (NMR), and Differential Scanning Calorimetry (DSC). The ability of VESylated‐FMN to promote adipogenesis and ameliorate insulin resistance brought on by oxidative stress was evaluated in differentiated preadipocytes. Interestingly, VESylated‐FMN promoted intracellular glucose absorption, which in turn increased lipid and triglyceride accumulation and thereby encouraged adipogenesis. VESylated‐FMN attenuated oxidative stress and promoted cell survival by reducing reactive oxygen species (ROS) generation and reversing apoptosis. Additionally, VESylated‐FMN improved insulin sensitization by upregulating the gene and protein expression of insulin‐sensitizing markers. Overall, FMN in conjugation with vitamin E can effectively augment prior insulin sensitivity by reducing oxidative stress for efficient glycemic control in hyperglycemia. [ABSTRACT FROM AUTHOR]

Sorbitol was employed as the grafting agent to modify nano-silica by the hyperbranched reaction. The obtained carrier was further used to prepare immobilized 4-dimethylaminopyridine (DMAP), which was successfully applied to produce vitamin E succinate. Two crucial steps were systematically investigated during the preparation of hyperbranched loaded DMAP: the epoxy-alcohol addition and N-alkylation reactions. For the epoxy-alcohol addition reaction, the maximum hydroxyl content reached 8.89 mmol/g when the molar ratio of sorbitol to epoxide was 2.5:1, the reaction temperature was 55 °C, the stirring rate was 500 rpm, and the reaction time was 8 h. In the N-alkylation reaction, when the reaction time was 20 h, the reaction temperature was 130 °C, the molar ratio of MAP to K$_{2}$CO$_{3}$ was 1:1.5, the KI to MAP molar ratio was 1:1 and the stirring rate was 600 rpm, the highest loading of DMAP reached 5.17 mmol/g. The catalytic performance of the loaded DMAP with different branching levels was evaluated by the acetylation reaction. The highest catalytic activity was observed in the hyperbranched catalyst, which reached 24.97 mmol/h${\cdot }$g. Moreover, the stability of the prepared immobilized DMAP was significantly enhanced. After being used for ten batches, 94.9% of the catalytic activity retention rate was obtained.

AIM: To investigate the effect of protein kinase R-like endoplasmic reticulum kinase （PERK） on the endoplasmic reticulum stress （ERS） and autophagy induced by vitamin E succinate （VES） in human gastric cancer cells. METHODS: Human gastric cancer cell lines MKN28 and MKN45 were cultured in vitro, and the cell viability was detected by CCK-8 assay. The cells were treated with VES at different doses for 24 h. The mRNA expression levels of glucose-regulated protein 78（ GRP78） and beclin-1 were detected by qRT-PCR, while the protein levels of GRP78, microtubule-associated protein 1 light chain 3 （LC3）, beclin-1 and PERK were detected by Western blot. After inhibiting PERK with 2 μmol/L GSK2606414 （GSK）, the cells were divided into control group, GSK group, VES group and VES+GSK group, and Western blot was used to detect the expression levels of PERK, GRP78, LC3 and beclin-1. RESULTS: The results of CCK-8 assay illustrated that VES significantly inhibited the viability of the two human gastric cancer cell lines （P< 0. 01）. The qRT-PCR results showed that beclin-1 and GRP78 mRNA expression levels in both cell lines were increased in a dose-dependent manner in response to VES （P<0. 05）. The Western blot results revealed that VES significantly increased the expression levels of GRP78, PERK, LC3 and beclin-1 compared with control group （P<0. 05）. The Western blot results also showed that the ratio of p-PERK/PERK in the two cell lines was decreased drastically in VES+GSK group （P<0. 05）, and the expression levels of GPR78, LC3 and beclin-1 proteins in VES+GSK group were significantly decreased compared with VES group （P<0. 05）. CONCLUSION: Vitamin E succinate activates ERS and autophagy in human gastric cancer cells, and PERK is involved in the regulation of ERS and autophagy induced by VES. [ABSTRACT FROM AUTHOR]

Sorbitol was employed as the grafting agent to modify nano-silica by the hyperbranched reaction. The obtained carrier was further used to prepare immobilized 4-dimethylaminopyridine (DMAP), which was successfully applied to produce vitamin E succinate. Two crucial steps were systematically investigated during the preparation of hyperbranched loadedDMAP: the epoxy-alcohol addition and N-alkylation reactions. For the epoxy-alcohol addition reaction, the maximum hydroxyl content reached 8.89 mmol/g when the molar ratio of sorbitol to epoxide was 2.5:1, the reaction temperature was 55 °C, the stirring ratewas 500 rpm, and the reaction timewas 8 h. In theN-alkylation reaction, when the reaction timewas 20 h, the reaction temperature was 130 °C, the molar ratio of MAP to K2CO3 was 1:1.5, the KI to MAP molar ratio was 1:1 and the stirring rate was 600 rpm, the highest loading of DMAP reached 5.17mmol/g. The catalytic performance of the loaded DMAP with different branching levels was evaluated by the acetylation reaction. The highest catalytic activity was observed in the hyperbranched catalyst, which reached 24.97 mmol/h·g. Moreover, the stability of the prepared immobilizedDMAPwas significantly enhanced. After being used for ten batches, 94.9% of the catalytic activity retention rate was obtained. [ABSTRACT FROM AUTHOR]

Nanocarriers have emerged as a promising cancer drug delivery strategy. Multi-drug resistance caused by overexpression of multiple-drug excretion transporters in tumor cells is the major obstacle to successful chemotherapy. Vitamin E derivatives have many essential functions for drug delivery applications, such as biological components that are hydrophobic, stable, water-soluble enhancing compounds, and anticancer activity. In addition, vitamin E derivatives are also effective mitocan which can overcome multi-drug resistance by binding to P glycoproteins. Here, we developed a carboxymethyl chitosan/vitamin E succinate nano-micellar system (O-CMCTS-VES). The synthesized polymers were characterized by Fourier Transform IR, and 1H NMR spectra. The mean sizes of O-CMCTS-VES and DOX-loaded nanoparticles were around 177 nm and 208 nm. The drug loading contents were 6.1%, 13.0% and 10.6% with the weight ratio of DOX to O-CMCTS-VES corresponding 1:10, 2:10 and 3:10, and the corresponding EEs were 64.3%, 74.5% and 39.7%. Cytotoxicity test, hemolysis test and histocompatibility test showed that it had good biocompatibility in vitro and in vivo. Drug release experiments implied good pH sensitivity and sustained-release effect. The DOX/O-CMCTS-VES nanoparticles can be efficiently taken up by HepG2 cancer cells and the tumor inhibition rate is up to 62.57%. In the in vivo study by using H22 cells implanted Balb/C mice, DOX/O-CMCTS-VES reduced the tumor volume and weight efficiently with a TIR of 35.58%. The newly developed polymeric micelles could successfully be utilized as a nanocarrier system for hydrophobic chemotherapeutic agents for the treatment of solid tumors.

A new multifunctional emulsifier was synthesized by coupling maltodextrin with a dextrose equivalent of 19 to vitamin E succinate. Two emulsifiers with varying degrees of vitamin E succinate substitution were prepared based on different mass ratios of vitamin E succinate to maltodextrin. The molecular structure and purity of these emulsifiers were analyzed. Nanoemulsions were prepared using octenyl succinic anhydride modified starch as a control to investigate the physical stability, antioxidant capacity, oxidative stability, and in vitro simulated digestive properties of the nanoemulsions. The emulsifying and antioxidant activity of the maltodextrin-vitamin E succinate conjugate was significantly superior to that of octenyl succinic anhydride modified starch, demonstrating good physical and oxidative stability. Additionally, they were rapidly digested under simulated small intestinal conditions. This new emulsifier shows broad application potential for the encapsulation, protection, and delivery of hydrophobic bioactive substances in the fields of medicine, food, and healthcare products. [Display omitted] • A novel emulsifier was synthesized from maltodextrin and vitamin E succinate. • This emulsifier enhances antioxidant activity and stabilizes O/W nanoemulsions. • This multifunctional emulsifier is biodegradable, safe, and applicable to foods. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) is the main challenge faced by cancer chemotherapy. Drug-conjugate offers a promising strategy for breast cancer therapy. In this regard, we developed a DNVM multifunctional drug delivery system by crosslinking doxorubicin (DOX) and vitamin E succinate (VES) with a pH-sensitive hydrazone bond and then encapsulated the DOX-NN-VES prodrug into pH-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine (HOD) micelles. DOX resistant MCF-7/ADR cell were adopted as a model to study the capability and mechanism of MDR reversal. DNVM exhibited much higher cytotoxicity and cell uptake efficiency compared with that of acid-insensitive DOX-VES loaded HOD micelles (DVSM) and DOX loaded HOD micelles (DOXM), indicating the better capacity of DNVM for the reversal of MDR. Moreover, DNVM prevented drug efflux more effectively, inhibited the expression of P-gp, induced excessive production of reactive oxygen species and affected the expression of apoptosis-related proteins. In vivo experiments showed that DNVM significantly inhibited the tumor growth with no obvious changes in the body weight of MCF-7/ADR cells-bearing nude mice. The results suggested that the "double gain" DNVM can synergistically enhance the efficacy of chemotherapeutics for DOX resistant tumor cells and has the potential to overcome tumor MDR. A dual-functional pH-sensitive doxorubicin - vitamin E succinate prodrug was developed and loaded into tumor microenvironment-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine micelle system (DNVM) for sequencing stimuli-release and overcoming doxorubicin resistance. The "double gain" DNVM can synergistically enhance the efficacy of chemotherapeutics for doxorubicin resistant tumor cells and has the potential to overcome tumor multiple drug resistance. [Display omitted] [ABSTRACT FROM AUTHOR]

Inducing mitochondrial malfunction is an appealing strategy to overcome tumor multidrug resistance (MDR). Reported here a versatile mitochondrial-damaging molecule, vitamin E succinate (VES), is creatively utilized to assist MDR reversal of doxorubicin hydrochloride (DOX·HCl) via a nanovesicle platform self-assembled from amphiphilic polyphosphazenes containing pH-sensitive 1H-benzo-[d]imidazol-2-yl) methanamine (BIMA) groups. Driven by multiple non-covalent interactions, VES is fully introduced into the hydrophobic membrane of DOX·HCl-loaded nanovesicles with loading content of 23.5%. The incorporated VES also offers robust anti-leakage property toward DOX·HCl under normal physiological conditions. More importantly, upon release within acidic tumor cells, VES can target mitochondria and result in various dysfunctions including excessive generation of reactive oxygen species (ROS), mitochondrial membrane potential (Δ Ψ m) loss, and inhibited adenosine triphosphate (ATP) synthesis, which contribute to cell apoptosis and insufficient energy supply for drug efflux pumps. Consequently, the killing-effect of DOX·HCl is significantly enhanced toward drug resistant cancer cells at the optimal mass ratio of DOX·HCl to VES. Further in vivo antitumor investigation on nude mice bearing xenograft drug-resistant human chronic myelogenous leukemia K562/ADR tumors verifies the extremely enhanced anti-tumor efficacy of the dual drug-loaded nanovesicle with the tumor inhibition rate (TIR) of 82.38%. Collectively, this study provides a s safe, facile and promising strategy for both precise drug delivery and MDR eradication to improve cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Receptor-mediated active targeting and tumor microenvironment responsive systems from polymeric micelles have been studied for rapid cellular internalization and triggered drug release. Previously we have constructed redox-responsive polymeric micelles composed of vitamin E succinate conjugated hyaluronic acid (HA-ss-TOS), which are able to actively target CD44 proteins and quickly release loaded drugs upon exposure to high levels of glutathione (GSH) in tumor cells. In the present study, we found that despite different cellular internalization mechanisms, micelles showed strong antineoplastic effects on 4T1 and B16F10 cells due to redox responsiveness. HA-ss-TOS-PTX micelles exhibited an excellent tumor targeting ability and prolonged retention time compared to Taxol in vivo. In addition, a superior antitumor effect was achieved compared to PTX-loaded insensitive micelles (HA-TOS-PTX) and Taxol. Our results revealed that PTX-loaded HA-ss-TOS micelles could enhance the antineoplastic efficacy of PTX for breast cancer and melanoma treatment and, thus, deserve further attention.

BACKGROUND: In order to improve the stability of vitamin E and broaden its scope of application, an effective solution is to convert vitamin E into its derivatives. This work developed a new Candida rugosa lipase (CRL) nanogel based on modification of ionic liquid with vinyl functional groups. This novel CRL nanogel was used in the preparation process of vitamin E succinate based on the principle of non‐aqueous enzymology. At the same time, various factors including enzyme concentration, substrate molar ratio, reaction temperature and reaction time, that affect the yield of vitamin E succinate were optimized and analyzed. RESULTS: Different solvents with various hydrophobicity parameters (LogP values) from −1.3 to 3.5 were studied, it was found that dimethyl sulfoxide (DMSO) had the lowest LogP value among organic solvents but vitamin E succinate had the highest yield in DMSO. Furthermore, the effect of different operating conditions, such as molar ratios of substrate, enzyme concentration, reaction temperature and reaction time was studied. Under the optimal process conditions (enzyme concentration 6 mg mL−1, substrate molar ratio 4:1, reaction temperature 55 °C and reaction time 15 h), the product yield was 62.58 ± 1.16%. CRL and CRL nanogel were characterized using Fourier‐transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM). It was shown that CRL nanogel influenced the catalytic behavior of lipase significantly by changing the structure and surface properties of CRL. CONCLUSION: Novel lipase nanogel was an excellent biocatalyst for enzymatic synthesis of vitamin E succinate. © 2020 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Gastric cancer is the most common malignant tumor disease in the human digestive system. It ranks first in the incidence of cancer-related diseases in China. It is a serious threat to the health of Chinese people. Vitamin E Succinate is a natural Vitamin E derivative and has been confirmed to have an inhibitory effect on tumor cell growth. Based on this, the article explores the effect of Vitamin E Succinate on inhibiting the growth of human gastric cancer cells and aims to provide a reference for the clinical diagnosis and treatment of gastric cancer. This article first systematically introduces Vitamin E Succinate and the related theoretical knowledge of gastric cancer and lays a sufficient theoretical foundation for the following research on Vitamin E Succinate inhibiting the growth of human gastric cancer cells and inducing apoptosis of gastric cancer cells. The human gastric cancer cell specimens and Vitamin E Succinate solution were formulated and the effect of Vitamin E Succinate on the growth of human gastric cancer cells was tested. According to the concentration of Vitamin E Succinate, the gastric cancer cells in the experiment were divided into Vitamin E Succinate 10 mg/ml dose group, Vitamin E Succinate 10 mg/ml dose group, Vitamin E Succinate 15 mg/ml dose group and the blank control group, the growth curve of gastric cancer cells, cell colony determination, cell division index determination and cell 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide detection and analysis were used to compare the changes in cell growth between different dose groups; the final result is that Vitamin E Succinate has a significant inhibitory effect on the growth of gastric cancer cells (p<0.05)and as the dose concentration increases and the treatment time increases, its inhibitory effect on the cells is more significant. [ABSTRACT FROM AUTHOR]

Catalytic efficiency in synthesis of vitamin E succinate was dramatically increased via the preparation of robust catalyst and the improvement of reaction system. 4-dimethylaminopyridine (DMAP) was covalently immobilized on nano-SiO2 to avoid the catalyst contamination of the product and permit the easy recycling of DMAP. Then, a hexane-acetone mixed solvent system was firstly introduced to replace the traditional single-solvent system, which was employed to improve the activity of immobilized DMAP derivative and the substrate solubility of the reaction system. The highest vitamin E succinate yield of 94% was achieved. In addition, the recyclability and stability of the immobilized DMAP derivative was excellent, the yield of vitamin E succinate had no obvious loss and remained 90% after recycling 20 times. The excellent results make this technology be a promising candidate for the industrial production of vitamin E succinate.

Receptor-mediated active targeting and tumor microenvironment responsive systems from polymeric micelles have been studied for rapid cellular internalization and triggered drug release. Previously we have constructed redox-responsive polymeric micelles composed of vitamin E succinate conjugated hyaluronic acid (HA-ss-TOS), which are able to actively target CD44 proteins and quickly release loaded drugs upon exposure to high levels of glutathione (GSH) in tumor cells. In the present study, we found that despite different cellular internalization mechanisms, micelles showed strong antineoplastic effects on 4T1 and B16F10 cells due to redox responsiveness. HA-ss-TOS-PTX micelles exhibited an excellent tumor targeting ability and prolonged retention time compared to Taxol in vivo. In addition, a superior antitumor effect was achieved compared to PTX-loaded insensitive micelles (HA-TOS-PTX) and Taxol. Our results revealed that PTX-loaded HA-ss-TOS micelles could enhance the antineoplastic efficacy of PTX for breast cancer and melanoma treatment and, thus, deserve further attention. [ABSTRACT FROM AUTHOR]

Background: The relative low stability, reusability and activity of enzymes made the industrial production of vitamin E succinate (VES) can only be performed with complex processes and high cost using chemical methods. To address these issues, in the present study, an ionic liquids (ILs) modification strategy was developed to improve the activity and stability of lipases in VES synthesis., Results: The results showed that the [1-butyl-3-methyl imidazole] [N-acetyl-l-proline] ILs modified Candida rugosa lipase (CRL) has the highest modification degree (48.28%), activity (774 U g -1 ), thermostability and solvent tolerance in three selected modifiers. Additionally, after reaction condition optimization, the highest yield of VES can be improved to 95.18% at 45 °C for 15 h, which was significantly improved compared to some previous studies., Conclusion: In the present study, a high-efficiency VES synthesis strategy was successfully developed via modification of lipase. Moreover, the mechanism by which ILs modification can enhance the activity and stability of lipase was investigated via both experimental and computational-aided methods. Molecular dynamics simulation suggested that ILs modification changed the geometry of Phe344 from flat to upright, which significantly reshaped and enhanced the size of substrate binding pocket of CRL. It is also agreement with our circular dichroism and fluorescence spectroscopy results, which suggested that the modification changed the secondary structure of CRL to a certain extent. The larger pocket also endowed the suitable binding pose of succinate, which made the hydrogen bonds between succinate and active site Ser209 become stronger, and thus improving the yield of VES. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Heparosan is a natural precursor of heparin biosynthesis in mammals. It is stable in blood circulation but can be degraded in lysosomes, showing good biocompatibility and long circulation features. So heparosan can be designed as anticancer drug carriers to increase tumor selectivity and improve the therapeutic effect. A novel redox-sensitive heparosancystamine- vitamin E succinate (KSV) micelle system was constructed for intracellular delivery of doxorubicin (DOX). Simultaneously, the redox-insensitive heparosan-adipic acid dihydrazide-vitamin E succinate copolymer (KV) was synthesized as control. DOX-loaded micelles (DOX/KSV) with an average particle size of 90-120 nm had good serum stability and redox-triggered depolymerization. In vitro drug release test showed that DOX/KSV micelles presented obvious redox-triggered release behavior compared with DOX/KV. Cytotoxicity and cell uptake were investigated using MGC80-3 tumor cells and COS7 fibroblast-like cells. The cell survival rate of blank micelles was more than 90%, and the cytotoxicity of DOX/KSV in MGC80-3 cells was higher than in COS7 cells, indicating that the carrier has better biocompatibility and less toxicity side effect. The cytotoxicity of DOX/KSV against MGC80-3 cells was significantly greater than that of free DOX and DOX/KV. Furthermore, compared with DOX/KV in MGC80-3 cells, DOX/KSV micelles uptook more anticancer drugs and then released DOX faster into the cell nucleus. The micelles were endocytosed by multiple pathways, but clathrin-mediated endocytosis was the main pathway. Therefore, heparosan polysaccharide could be a potential option as anticancer carrier for enhancing efficacy and mitigating toxicity. [ABSTRACT FROM AUTHOR]

• A high-efficiency and sustainable strategy of enzymatic synthesis of vitamin E succinate was successfully developed. • A synergistic effect of deep eutectic solvents and lipase was found and investigated. • DESs enhanced the electrophilicity of succinic anhydride and promoted the reaction via hbonds. • DESs improved the capacity of capturing and locating substrate of CRL via hbonds. The low tolerance of lipases in organic solvents limits the industrial applications of enzymatic synthesis of Vitamin E succinate (VES). In this study, the deep eutectic solvents (DESs) were adopted as mediums to achieve the high efficiency and low-cost enzymatic synthesis of VES. Several kinds of commonly used DESs, including hydrophilic and hydrophobic DESs were screened firstly and fortunately found that the decanoic acid: lidocaine (DecA: Lid 2:1) performed best in the enzymatic synthesis of VES with a yield of 98.21 ± 0.63 % at 50 ℃ in only 6 h, which was significantly improved compared to previous studies. Interestingly, a synergistic effect of lipase and DESs was found in the enzymatic synthesis of VES, and the results of molecular simulations and density functional calculation suggested that it can be attributed to that 1) the hydrogen bonds interaction between DecA:Lid (2:1) and succinic anhydride enhances the electrophilicity of succinic anhydride and promotes the esterification reaction, 2) DecA:Lid (2:1) causes conformational changes of CRL via hydrogen bonds, which improves its capacity to capture and locate substrate molecules and thus enhancing its catalytic efficiency. [ABSTRACT FROM AUTHOR]

Vitamin E succinate (VES) is an esterified form of natural α-tocopherol, has turned out to be novel anticancer agent. However, its anticancer mechanisms have not been illustrated. Previously, we reported VES mediated Ca2+ release from the endoplasmic reticulum (ER) causes mitochondrial Ca2+ overload, leading to mitochondrial depolarization and apoptosis. Here, we elucidated the mechanism of VES-induced Ca2+ transfer from ER to mitochondria by investigating the role of VES in ER-mitochondria contact formation. Transmission electron microscopic observation confirms VES mediated ER-mitochondria contact while fluorescence microscopic analysis revealed that VES increased mitochondria-associated ER membrane (MAM) formation. Pre-treatment with the inositol 1,4,5-triphosphate receptor (IP 3 R) antagonist 2-aminoethyl diphenylborinate (2-APB) decreased VES-induced MAM formation, suggesting the involvement of VES-induced Ca2+ efflux from ER in MAM formation. The ER IP 3 R receptor is known to interact with voltage-dependent anion channels (VDAC) via the chaperone glucose-regulated protein 75 kDa (GRP75) to bring ER and mitochondria nearby. Although we revealed that VES treatment does not affect GRP75 protein level, it increases GRP75 localization in the MAM. In addition, the inhibition of Ca2+ release from ER by 2-APB decreases GRP75 localization in the MAM, suggesting the possibility of Ca2+-induced conformational change of GRP75 that promotes formation of the IP 3 R-GRP75-VDAC complex and thereby encourages MAM formation. This study identifies the mechanism of VES-induced enhanced Ca2+ transfer from ER to mitochondria, which causes mitochondrial Ca2+ overload leading to apoptosis. • Vitamin E succinate (VES) induces mitochondrial Ca2+ overload. • Ca2+ overload due to enhanced Ca2+ transfer from ER to mitochondria. • Ca2+ transfer is facilitated by VES induced MAM formation. • VES induced GRP75 localization in the MAM aids IP 3 R-GRP75-VDAC complex formation. [ABSTRACT FROM AUTHOR]

Yuling Liu,1,* Yingqi Xu,2,* Minghui Wu,3 Lijiao Fan,1 Chengwei He,2 Jian-Bo Wan,2 Peng Li,2 Meiwan Chen,2 Hui Li11Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, People’s Republic of China; 3Department of Cell Biology and Anatomy, School of Medicine, University of Florida, Gainesville, FL, USA *These authors contributed equally to this work Abstract: Mitoxantrone (MIT) is a chemotherapeutic agent with promising anticancer efficacy. In this study, Pluronic F68-vitamine E succinate (F68-VES) amphiphilic polymer micelles were developed for delivering MIT and enhancing its anticancer activity. MIT-loaded F68–VES (F68–VES/MIT) micelles were prepared via the solvent evaporation method with self-assembly under aqueous conditions. F68–VES/MIT micelles were found to be of optimal particle size with the narrow size distribution. Transmission electron microscopy images of F68–VES/MIT micelles showed homogeneous spherical shapes and smooth surfaces. F68–VES micelles had a low critical micelle concentration value of 3.311 mg/L, as well as high encapsulation efficiency and drug loading. Moreover, F68–VES/MIT micelles were stable in the presence of fetal bovine serum for 24 hours and maintained sustained drug release in vitro. Remarkably, the half maximal inhibitory concentration (IC50) value of F68–VES/MIT micelles was lower than that of free MIT in both MDA-MB-231 and MCF-7 cells (two human breast cancer cell lines). In addition, compared with free MIT, there was an increased trend of apoptosis and cellular uptake of F68–VES/MIT micelles in MDA-MB-231 cells. Taken together, these results indicated that F68–VES polymer micelles were able to effectively deliver MIT and largely improve its potency in cancer therapy. Keywords: F68, vitamin E succinate, mitoxantrone, polymer micelles, cancer therapy

Abstract In this work, we presented a facile and novel strategy, chelation–assisted in situ self-assembly, to prepare the loose polyacrylonitrile (PAN)–based nanocomposite membrane for dye desalination. Based on the chelate reaction polyethyleneimine (PEI) with metal ions, an Ag+–PEI complex layer was deposited onto the hydrolyzed PAN surface. Then, the chelate complex layer was served as the templates to in-situ synthesize the vitamin E succinate (VES)-functionalized AgCl nanoparticles，which were uniformly distributed on the membrane surface and provided additional transport pathways for water molecules. The prepared nanocomposite membrane achieved the permeability of 106.4, 101.2 and 92.3 L m−2 h−1 MPa−1, which was 20–50% higher in comparison with that of the pure Ag+–PEI@HPAN membrane, with corresponding rejections of 99.2%, 99.5% and 99.8% to crystal violet, acid fuchsin and congo red solution at the concentration of 0.1 g L−1. Meanwhile, this membrane possessed a low inorganic salts rejection (6.2%, 9.6% 8.3% and 12.8% for MgCl 2 , NaCl, MgCl 2 and Na 2 SO 4) and good stability during the 60 h filtration of dye-salt mixture. We anticipate that this novel route could be applied to prepare the polymer-supported nanocomposite membrane with enhanced separation performance. Graphical abstract fx1 Highlights • A novel and facile chelation–assisted in situ self-assembly route was proposed. • The prepared loose PAN–based nanocomposite membrane exhibited good dye desalination ability. • The uniformly distributed nanoparticles enhanced the separation performance. [ABSTRACT FROM AUTHOR]

[Display omitted] • Polyglycerol vitamin E succinate (PG20-VES) is a promising multifunctional food additive. • PG20-VES is a surface-active substance with low CMC (3.2 μg/mL) and interfacial tension (28.1 mN/m). • PG20-VES can scavenge ABTS+ radicals and act as an antioxidant. • PG20-VES stabilized oil-in-water emulsion showed excellent physicochemical stability. α-Tocopherol, as an oil-soluble vitamin with strong antioxidant activity. It is the most naturally abundant and biologically active form of vitamin E in humans. In this study, a novel emulsifier (PG20-VES) was synthesized by attaching hydrophilic twenty-polyglycerol (PG20) to hydrophobic vitamin E succinate (VES). This emulsifier was shown to have a relatively low critical micelle concentration (CMC = 3.2 μg/mL). The antioxidant activities and emulsification properties of PG20-VES were compared with those of a widely used commercial emulsifier: D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS). PG20-VES exhibited a lower interfacial tension, stronger emulsifying capacity and similar antioxidant property to TPGS. An in vitro digestion study showed that lipid droplets coated by PG20-VES were digested under simulated small intestine conditions. This study showed that PG20-VES is an efficient antioxidant emulsifier, which may have applications in the formulation of bioactive delivery systems in the food, supplement, and pharmaceutical industries. [ABSTRACT FROM AUTHOR]

Severe toxicity and poor tumour penetration are two intrinsic limited factors to hinder the broad clinical application for most of first-line chemotherapeutics. In this study, a novel vitamin E succinate-grafted ε-polylysine (VES-g-PLL) polymer was synthesized by using ε-polylysine as backbone. By adjusting VES graft ratio, VES-g-PLL (50) with a theoretic VES graft ratio of 50% could self-assemble into a supermolecular micelle with a hydrodynamic diameter (D h ) of ca.20 nm, and Zeta potential of 19.6 mV. VES-g-PLL micelles themselves displayed a strong anti-tumour effect on glioma. The poorly water-soluble curcumin was effectively encapsulated in VES-g-PLL micelles with the drug loading amount and entrapment efficiency reaching 4.32% and 82.27%, respectively. In a physiologic medium, curcumin-loaded VES-g-PLL micelles (Cur-Micelles) not only remained stable without obvious drug leakage but also sustained the release of its encapsulated curcumin for a long time. Because of the ultra-small size and positively-charged surface, Cur-Micelles penetrated the deeper tumour zone than free curcumin, resulting in a significant inhibition of tumour spheroids growth. Moreover, in vivo strong antitumor effect of Cur-Micelles was also exhibited at assistance of ultrasound-targeted microbubble destruction and the real-time MRI imaging demonstrated a nearly complete suppression of glioma after 28 days of treatment. TUNEL staining showed that the therapeutic mechanism of Cur-Micelles was relevant to the apoptosis of tumour cells. Finally, in vivo nontoxicity of Cur-Micelles against normal organs including heart, liver, spleen, lung and kidney tissues was also demonstrated by the HE staining. In conclusion, VES-g-PLL micelles may serve as a potential carrier for curcumin to enhance tumour penetration and improve therapeutic effect on glioma. [ABSTRACT FROM AUTHOR]

Vitamin E succinate (VES), a unique selective anti-cancer drug, has attracted much attention for its ability to induce apoptosis in various cancer cells. Importantly, it has been reported that VES is largely non-toxic to normal cells. However, poor aqueous solubility and bioavailability extensively restricted its clinical utility. In this report, dual VES phospholipid conjugate (di-VES-GPC) prodrug based liposomes were prepared in order to develop an efficient delivery system for VES. Di-VES-GPC was first synthesized by conjugating VES with l -α-glycerophosphorylcholine (GPC) using N , N ′-dicyclohexylcarbodiimide (DCC) as a coupling agent. The di-VES-GPC prodrug was able to self-assemble into liposomes by reverse-phase evaporation method. The structure of the liposomes was characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM) and cryo-TEM. The results showed that di-VES-GPC assembled liposomes were spherical with an average diameter approximately 183 nm. Cryo-TEM data confirmed the formation of multilamellar liposomes with the bilayer thickness about 5 nm by the assembly of the conjugate without any excipient. The VES drug loading highly reaches up to 82.8 wt% in the liposomes after a simple calculation. Furthermore, the in vitro release behavior of di-VES-GPC liposomes was evaluated in different media. It was found that the liposomes could release free VES at a weakly acidic microenvironment but exhibited good stability under a simulated biological condition. The cellular uptake and intracellular drug release tests demonstrated that di-VES-GPC liposomes could be internalized effectively and converted into parent drug VES in cancer cells. Furthermore, in vitro antitumor activities of the di-VES-GPC liposomes were evaluated by MTT assay and flow cytometry. It was revealed that the liposomes presented comparable cytotoxicities to free VES. Taken together, the di-VES-GPC liposomes might provide an excellent formulation of VES which have potential in the treatment of cancers. [ABSTRACT FROM AUTHOR]

One of the strategies for improved therapeutic effects in cancer therapy is combination chemotherapy. In this study, a flexible nano-MOF (Fe-MIL-88B-NH 2 ) was synthesized in a sonochemical process, then co-loaded with α-tocopheryl succinate (TOS) and curcumin (CCM). The anticancer activity of co-loaded Fe-MIL-88B-NH 2 (Fe-MIL-88B-NH 2 /TOS@CCM) against the HeLa cells was compared with that of the single-loaded counterpart (Fe-MIL-88B-NH 2 @CCM). MTT analysis indicates improved cytotoxicity of Fe-MIL-88B-NH 2 /TOS@CCM. The data from the cell apoptosis assay indicated more apoptosis in the case of the co-loaded nano-MOF. This study indicates the positive effect of the presence of TOS on enhancing the anticancer effect of Fe-MIL-88B-NH 2 @CCM to prepare a more efficient drug delivery nanosystem., (© 2023 Wiley-VCH GmbH.)

Vitamin E succinate (VES), a derivative of vitamin E, is a promising cancer chemopreventive agent that inhibits tumor promotion by inducing apoptotic cell death. The effects of VES on autophagy, an intricate programmed process which helps cells survive in some stressed situations by degrading some cytoplasmic material, are unclear. When human gastric cancer cells SCG-7901 were exposed to VES, both the level of microtubule-associated protein 1 light chain 3 and the yeast ATG6 homolog Beclin-1 increased, and related autophagy genes were activated, thereby suggesting that autophagy was induced by VES. We also observed that VES-induced autophagy was accompanied by the activation of AMP-activated protein kinases (AMPK). VES-induced autophagy decreased when AMPK was inhibited by using small interfering RNA (siRNA), thereby suggesting that VES-induced autophagy is mediated by AMPK. Moreover, further studies revealed that the decreased activity of mammalian target of rapamycin (mTOR) and its downstream targets P70S6K and 4EBP-1 were involved in VES-activated autophagy associated with AMPK activation. The experiments also showed that the activity of protein kinases B (Akt)-mTOR axis was inhibited by VES. VES-induced AMPK activation could be attenuated by Akt activation. Overall, our studies demonstrated that AMPK was involved in the VES-induced autophagy. Crosstalk exists between AMPK and the Akt/mTOR axis. The results elucidated the mechanism of VES-induced autophagy in human gastric cancer cells. [ABSTRACT FROM AUTHOR]

Esophageal cancer is the fourth most common gastrointestinal cancer, it generally has a poor prognosis and novel strategies are required for prevention and treatment. Vitamin E succinate (VES) is a potential chemical agent for cancer prevention and therapy as it exerts anti-tumor effects in a variety of cancers. However, the role of VES in tumorigenesis and progression of cancer remains to be elucidated. The present study aimed to determine the effects of VES in regulating the survival and apoptosis of human esophageal cancer cells. EC109 human esophageal cancer cells were used to investigate the anti-proliferative effects of VES. The MTT and Annexin V-fluorescein isothiocyanate/propidium iodide assays demonstrated that VES inhibited cell proliferation and induced apoptosis in esophageal cancer cells. Furthermore, VES downregulated constitutively active basal levels of phosphorylated (p)-serine-threonine kinase AKT (AKT) and p-mammalian target of rapamycin (mTOR), and decreased the phosphorylation of AKT substrates Bcl-2-associated death receptor and caspase-9, in addition to mTOR effectors, ribosomal protein S6 kinase β1 and eIF4E-binding protein 1. Phosphoinositide-3-kinase (PI3K) inhibitor, LY294002 suppressed p-AKT and p-mTOR, indicating PI3K is a common upstream mediator. The apoptosis induced by VES was increased by inhibition of AKT or mTOR with their respective inhibitor in esophageal cancer cells. The results of the present study suggested that VES targeted the PI3K/AKT signaling pathways and induced apoptosis in esophageal cancer cells. Furthermore, the current study suggests that VES may be useful in a combinational therapeutic strategy employing an mTOR inhibitor. [ABSTRACT FROM AUTHOR]

• Administration of VES, alone or in combination with MSA, in HDMTX and FA receiving mice achieved better chemotherapy outcomes. • Administration of VES along with HDMTX and FA in 4 T1 tumor-bearing BALB/c mice inhibited tumor metastasis and also induced tumor shrinkage. • Also, the treatments caused induction and suppression of FOXP3 mRNA in the tumor and spleen, respectively. We aimed to evaluate the anti-cancer and immune system enhancing properties of Vitamin E succinate (VES) and methylselenic acid (MSA) administration on 4T1 breast tumor model under high-dose methotrexate (HDMTX) therapy and folinic acid (FA) rescue. Thirty six 4T1 mammary carcinoma bearing mice were randomly divided into six groups: control (untreated; n = 6), treatment-1 (T1 group; HDMTX; n = 6), T2 (T1 + FA; n = 6), T3 (T2 + MSA; n = 6), T4 (T2 + VES; n = 6) and T5 (T3 + VES; n = 6). On day 21 of the study, all surviving mice were sacrificed and primary tumors and peripheral tissues were examined for histological and gene expression assays. The expression of GATA Binding Protein-3 (GATA3), forkhead box-P3 (FOXP3), T-bet and Retinoic acid receptor-related orphan receptor γt (RORγt) were evaluated in tumors and spleens. Also, vascular endothelial growth factor-A (VEGF-A) and UL16-Binding Protein 1 (ULBP-1) expression were evaluated in tumors. The control, T4 and T5 groups were able to complete the entire 21-day study period. Also, significant tumor shrinkage was occurred in T4 group (P < 0.05). Suppression of splenic FOXP3 and GATA3 were observed in the mice receiving T4 and T5 regimens. Also, induction of tumoral FOXP3 and GATA3 were achieved in the T4 and T5 groups, respectively (P < 0.05). No metastasis occurred in T4 receiving group; while, lung and liver metastasis were observed in T5 group. In this study, high and fixed dose of MTX was used. Further studies are needed to optimize MTX dose along with FA, VES and MSA. [ABSTRACT FROM AUTHOR]

Objective: To investigate the role of inositol-requiring enzyme 1(IRE1) in autophagy of human gastric cancer cells induced by vitamin E succinate(VES)., Methods: Human gastric cancer SGC-7901 cells were cultured in vitro and divided into solvent control group(0.1% ethanol absolute), different doses(5, 10, 15 and 20 μg/mL) VES group, 4μ8C group, and VES + 4μ8C group. The endoplasmic reticulum stress-related molecules glucose regulated protein 78(GRP78) and C/EBP homologous protein(CHOP), autophagy marker microtubule associated Protein1 light chain 3(LC3), Beclin-1, unfolded protein response branching pathway Inositol-requiring enzyme 1(IRE1), X box-binding protein 1(XBP1), c-Jun n-terminal kinase(JNK) and p-JNK were detected by Western blot in the solvent control group and different doses of VES group. IRE1 was inhibited by 4μ8C. The expressions of IRE1, XBP1, JNK, p-JNK, GRP78 and CHOP were detected by Western blot, and the expressions of LC3 and Beclin-1 were detected., Results: The expression of GRP78(1.16±0.06) and CHOP(1.36±0.11) in 20 μg/mL VES group were significantly higher than those in solvent control group GRP78(0.36±0.10) and CHOP(0.48±0.05)(P&lt;0.001). The expression of Beclin-1(1.09±0.20) and LC3-Ⅱ/LC3-Ⅰ(1.29±0.03) in 20 μg/mL VES group were significantly higher than those in solvent control group(0.27±0.07) and LC3-Ⅱ/LC3-Ⅰ(0.43±0.06)(P&lt;0.001). The expression levels of IRE1(1.07±0.20), XBP1(1.33±0.07) and p-JNK/JNK(1.19±0.31) in 20 μg/mL VES group were significantly higher than those in the solvent control group(P&lt;0.01). After IRE1 is inhibited: The expression level of IRE1(0.63±0.27), XBP1(0.74±0.09), p-JNK/JNK(0.35±0.04), GRP78(0.66±0.02), CHOP(0.51±0.02), LC3-Ⅱ/LC3-Ⅰ(0.72±0.01), Beclin-1(0.70±0.15) was significantly lower than that of VES group(P&lt;0.05)., Conclusion: VES may participate in the regulation of autophagy in gastric cancer cells by upregulating IRE1 pathway.

Abstract: Vitamin E succinate (TOS) modified pluronic micelles (PF-TOS micelles) were prepared to be used as a vehicle for paclitaxel (PTX). The average size of resultant PTX-loaded PF-TOS micelles (PF-TOS-PTX-micelles) was about 58nm. PF-TOS-PTX-micelles showed enhanced encapsulation efficiency and better stability as compared to the non-modified controls. Fluorescence microscopy and high performance liquid chromatography studies showed that PTX-loaded PF-TOS micelles had excellent cellular uptake ability by human glioma U87 cells. Cytotoxicity assay revealed that PTX-loaded PF-TOS micelles demonstrated higher anti-cancer activity to U87 cells than that of the non-modified PF micelles. Pharmacokinetic studies indicated the longer systemic circulation time and slower plasma elimination rate in PTX-loaded PF-TOS micelles than that of the non-modified controls. In vivo tissue distribution studies showed that PTX-loaded PF-TOS micelles were preferably accumulated in spleen and liver. Taken together, the results evidently indicated that PF-TOS micelles improve the hydrophobic chemotherapeutic drugs delivery by means of efficient encapsulation and stabilization for anti-tumor therapy. [Copyright &y& Elsevier]

Abstract: A star-shape copolymer of nanostructure-forming material, P-glycoprotein (P-gp) reversible inhibitor and anticancer enhancer, lysine-linked di-tocopherol polyethylene glycol 2000 succinate (PLV2K), was synthesized to overcome multidrug resistance (MDR) in cancer chemotherapy. The critical micellar concentration of PLV2K was as low as 1.14 μg/mL, which can endow nanoassemblies good physical stability. Doxorubicin (DOX) was encapsulated into the hydrophobic core of PLV2K (PLV2K-DOX), with encapsulation efficiency as high as 94.5% and a particle size of 16.4 nm. DOX released from PLV2K-DOX nanomicelles was pH-dependent, which ensures micelles stable in blood circulation and releases DOX within tumor cells. Facilitated by the cytotoxicity and uncompetitive P-gp ATPase inhibition by PLV2K, PLV2K-DOX showed greater cytotoxicity compared with DOX solution with increased intracellular accumulation in resistant MCF-7/Adr cells. PLV2K-DOX nanomicelles were uptaken into MCF-7/Adr cells via macropinocytosis and caveolae-mediated endocytosis, which further facilitate escapement of P-gp efflux. The anticancer efficacy in vivo was evaluated in 4T1-bearing mice and inhibition of tumor by PLV2K-DOX was more effective than TPGS-DOX and DOX solution. In summary, PLV2K copolymer has striking functions such as uncompetitive P-gp ATPase reversible inhibitor and anticancer efficacy, and could be a promising nanocarrier in improving the chemotherapy of hydrophobic anticancer drugs. [Copyright &y& Elsevier]

Abstract: Vitamin E succinate (RRR-α-tocopheryl succinate, VES), an efficient inducer of apoptosis, acts as a potent agent for cancer therapy. However, the mechanism by which VES mediates the effects are not yet fully understood. Here we studied the effect of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) on VES-induced apoptosis of SGC-7901 human gastric cancer cells. VES caused cytological changes typical of apoptosis, increased ER dilation and cytosolic Ca2+ concentration. And endogenous ER stress markers, GRP78 and GRP94 were transcriptionally and translationally altered. In response to VES, induction of CHOP, activation of caspase-4 and JNK were observed. Furthermore, VES also triggered activation of UPR components, including RNA-dependent protein kinase (PKR)-like ER kinase (PERK), activating transcription factor 6 (ATF6), X-box-binding protein 1 (XBP1), and ATF4 in a concentration- and time-dependent manner. Consequently, our results suggest that VES-induced apoptosis is coupled to ER stress and UPR activation in SGC-7901 human gastric cancer cells. [Copyright &y& Elsevier]

Mitocans are drugs selectively killing cancer cells by destabilizing mitochondria and many induce apoptosis via generation of reactive oxygen species (ROS). However, the molecular events by which ROS production leads to apoptosis has not been clearly defined. In this study with the mitocan α-tocopheryl succinate (α-TOS) the role of the Bcl-2 family proteins in the mechanism of malignant cell apoptosis has been determined. Exposure of several different cancer cell lines to α-TOS increased expression of the Noxa protein, but none of the other proteins of the Bcl-2 family, an event that was independent of the cellular p53 status. α-TOS caused a profound conformational change in the pro-apoptotic protein, Bak, involving oligomerization in all cell types, and this also applied to the Bax protein, but only in non-small cell lung cancer cells. Immunoprecipitation studies indicated that α-TOS activates the two BH1-3 proteins, Bak or Bax, to form high molecular weight complexes in the mitochondria. RNAi knockdown revealed that Noxa and Bak are required for α-TOS-induced apoptosis, and the role of Bak was confirmed using Bak- and/or Bax-deficient cells. We conclude that the major events induced by α-TOS in cancer cells downstream of ROS production leading to mitochondrial apoptosis involve the Noxa-Bak axis. It is proposed that this represents a common mechanism for mitochondrial destabilization activated by a variety of mitocans that induce accumulation of ROS in the early phases of apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: We studied the effects of isoflavones and irradiation on cell cycle in a human salivary gland cell line (HSG). Genistein and a soy isoflavone conjugate (NS) inhibited DNA synthesis. Cells deconjugated the glucoside form of isoflavones in NS to the aglycones genistein and daidzein. NS, genistein and IR increased phosphorylation of p53 and p21CIP1 at serine 15 (phos-p53). Irradiation and NS also increased levels of p21CIP1. In a cologenic survival assay, cells in log phase growth had high radio-sensitivity with 2Gy causing a reduction in survival (SF2 =0.45). Conclusion: isoflavones and radiation may interact to sensitize cancer cells to radiation. [Copyright &y& Elsevier]

The objectives of the present research investigations were to (i) elucidate the mechanism for the oxidative degradation of Δ9-tetrahydrocannabinol (THC) in polymer matrix systems prepared by a hot-melt fabrication procedure, and (ii) study the potential for controlling these mechanisms to reduce the degradation of THC in solid dosage formulations. Various factors considered and applied included drug-excipient compatibility, use of antioxidants, cross-linking in polymeric matrices, microenvironment pH, and moisture effect. Instability of THC in polyethylene oxide (PEO)-vitamin E succinate (VES) patches was determined to be due to chemical interaction between the drug and the vitamin as well as with the atmospheric oxygen. Of the different classes and mechanisms of antioxidants studied, quenching of oxygen by reducing agents, namely, ascorbic acid was the most effective in stabilizing THC in PEO-VES matrices. Only 5.8% of the drug degraded in the ascorbic acid-containing patch as compared to the control (31.6%) after 2 months of storage at 40°C. This coupled with the cross-linking extent and adjustment of the pH microenvironment, which seemed to have an impact on the THC degradation, might be effectively utilized towards stabilization of the drug in these polymeric matrices and other pharmaceutical dosage forms. These studies are relevant to the development of a stable transmucosal matrix system for the therapeutic delivery of amorphous THC. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:2473–2485, 2006 [ABSTRACT FROM AUTHOR]

Abstract: There is compelling evidence for the cancer chemopreventive effects of vitamin E and related compounds. Of all the vitamin E derivatives that have been investigated to date, vitamin E acid succinate is the most effective anti-cancer agent. This report describes the preparation and testing of liposomal formulation of mono α-tocopheryl ester of succinic acid (α-TOS) for cytotoxicity against hamster cheek pouch carcinoma cell line (HCPC-1). Small unilamellar vesicles (SUV) of phosphatidylcholine incorporating 70μM α-TOS were superior to α-TOS alone or SUV without incorporated α-TOS, as inducers of apoptosis in HCPC-1 cells. Liposomal α-TOS perturbed the lipid structure in cells, promoted apoptosis, and decreased cell viability. The mechanism of action of α-TOS appears to involve membrane damage and induction of ceramide mediated apoptosis. [Copyright &y& Elsevier]

There is convincing evidence that vitamin E succinate significantly reduces human prostate cancer growth in experimental models compared with ɑ-tocopherol or tocopheryl acetate. Its intact delivery to cancer cells is questionable when administered orally; however, a study in transgenic mice showed a synergistic inhibitory effect of dietary vitamin E succinate, selenium, and lycopene on prostate cancer incidence. Clinical trials have yet to confirm this effect. [ABSTRACT FROM AUTHOR]

The antioxidant activities of RRR-vitamin E (VE), all-rac-vitamin E (all-rac-VE), trolox, RRR-vitamin E acetate (VEA), all-rac-vitamin E phosphate (VEP) and RRR-vitamin E succinate (VES) were compared. In this study, the rank order in the inhibition of lipid peroxidation (LPO) of VE and its derivatives was trolox>VE≈all-rac-VE>VEA>VES. VE and trolox inhibited LPO in non-heated and heated rat liver microsomes. It has generally been accepted that this is due to scavenging of free radicals by these antioxidants, and during this protection the antioxidants are oxidized. VEA and VES have to be converted into VE by esterases to obtain antioxidant activity against LPO. VEP, however, had a potent antioxidant effect of its own without conversion to VE. In contrast to VE, VEP is not consumed during this protection. Of the compounds tested, VEP is the most potent in induction of hemolysis of erythrocytes. EPR experiments using the spin label 16-doxylstearic acid showed that VEP reduces membrane fluidity, in contrast to VE. This indicates that VEP acts as a detergent and forms a barrier that might inhibit the transfer of radicals from one polyunsaturated fatty acid to another. This new mechanism may form the basis for a new class of antioxidants. [Copyright &y& Elsevier]

Apoptotic DNA fragmentation minimizes the risk of transferring genetic information from apoptotic cancer cells to the neighboring cells. We have reported previously that caspase-deficient human renal cell carcinoma (RCC) lines were almost completely resistant to apoptosis in response to cytotoxic agents. In the present report we examined apoptotic process in caspase competent RCC-91 cells. Apoptosis in RCC-91 cells was accompanied by activation of caspases-3 and -9; cleavage of PARP and DFF45 proteins; typical apoptotic nuclei fragmentation and mitochondrial collapse. Nevertheless, DNA in these cells was not degraded into oligonucleosomal fragments compared to control Jurkat cells. Expression of caspase-activated DNase, DFF40 accountable for characteristic ladder pattern was easily detectable in Jurkat but not renal cancer cells, providing one possible explanation for the lack of oligonucleosomal DNA fragmentation in apoptotic RCC cells. Lack of typical DNA fragmentation indicates a potential threat of transferring genetic information from one tumor cell to another or to the neighboring healthy cells. [Copyright &y& Elsevier]

α-Tocopheryl succinate (α-TOS), a redox-silent analogue of vitamin E, inhibits malignant mesotheliomas (MM) in a pre-clinical model. Here we investigated the underlying mechanism. Exposure of MM cells to α-TOS triggered apoptosis at higher and inhibited proliferation at lower concentrations, while this effect was not observed in non-malignant mesothelial cells. Sub-apoptotic doses of α-TOS caused down-regulation of fibroblast growth factor receptor-1 (FGFR1) selectively in MM cells, while the effect on FGFR2 was only marginal. FGF1 and FGF2 enhanced MM cell proliferation that was suppressed by α-TOS. Over-expression of E2F1, a transcriptional factor of FGFR1, but not its dominant-negative counterpart, partially blocked the inhibitory activity of α-TOS on MM cell proliferation. Our data suggest a novel mechanism by which a clinically intriguing agent selectively suppresses proliferation of cancer cells, as shown here for the untreatable mesotheliomas. [Copyright &y& Elsevier]

Though the etiology is not well understood, late-onset Parkinson''s disease (PD) appears to result from several key factors including exposure to unknown environmental toxicants, toxic endogenous compounds and genetic alterations. A plethora of scientific evidence suggest that these environmental and endogenous factors cause PD by producing mitochondrial (mito) oxidative stress and damage in the substantia nigra, leading to cell death. Thus assuming a critical role for mito oxidative stress in PD, therapies to treat or prevent PD must target these mito and protect them against oxidative damage. The focus of this article is to briefly review the experimental and clinical evidence for the role of environmental toxicants and mito oxidative stress/damage in PD as well as discuss the potential protective role of mito d-α-tocopherol (T) enrichment and vitamin E therapy in PD. New experimental data are presented that supports the enrichment of mito with T as a critical event in cytoprotection against toxic mito-derived oxidative stress. We propose that chronic, high dose vitamin E dietary supplementation or parenteral vitamin E administration (e.g. vitamin E succinate) may serve as a successful therapeutic strategy for the prevention or treatment of PD (by enriching substantia nigra mito with protective levels of T). [Copyright &y& Elsevier]

Relapse of melanoma after surgical treatment remains a significant clinical problem in need of novel therapies. Vitamin E succinate (VES) is a promising antitumor micronutrient. We evaluated the effect of VES on melanoma dormancy and angiogenesis. B16F10 melanoma cells were allografted in mice. The effect of VES on melanoma dormancy was measured by monitoring tumor volume. Tumor vascularity was quantitated with CD31 immunostaining. The expression of vascular endothelial growth factor (VEGF), VEGF receptor 1, and VEGF receptor 2 in tumors was assessed by the intensity of immunostaining. VES effect on secreted VEGF protein and VEGF promoter activity was measured with enzyme-linked immunosorbent assay and transient transfection assay, respectively. Significance was determined by analysis of variance. VES promoted melanoma dormancy ( P=.0019) and inhibited melanoma angiogenesis ( P<.0001). VES also significantly suppressed the expression of VEGF, VEGF receptor 1, and VEGF receptor 2 in melanoma tumors ( P<.0001). Melanoma VEGF secretion ( P=.0077) and melanoma VEGF promoter activity ( P<.05) were significantly inhibited by VES. VES promotes melanoma dormancy and inhibits melanoma angiogenesis. The mechanism of the VES antiangiogenesis effect involves the inhibition of VEGF gene transcription. These findings support future studies of VES in the prevention of melanoma metastasis. [ABSTRACT FROM AUTHOR]

Background. Vitamin E succinate (VES) is a promising anti-cancer micronutrient. In this study, we tested the hypothesis that VES will promote colon cancer tumor dormancy and inhibit liver metastases in colon cancer.Methods. CT-26 colon cancer cells were treated with VES in vitro and in an in vivo model of liver metastases. The impact of VES on cellular proliferation and apoptosis was measured in vitro by MTS assay and sandwich ELISA and in vivo by PCNA staining and TUNEL assay, respectively. Correlation coefficients and independent t tests were used for statistical analysis.Results. VES significantly and specifically inhibited cell proliferation (P = 0.011) and promoted apoptosis (P < 0.0074) of cancer cells in vitro. VES produced a 40% reduction of liver metastases (P = 0.037). Five of the eight mice had an excellent response to VES. Subsequent analysis of these five mice revealed a 75% reduction in the number of liver metastases (P < 0.05). VES significantly promoted tumor cell apoptosis (P < 0.0003) and inhibited cell proliferation (P = 0.0069) in vivo.Conclusions. VES inhibits the growth of colon cancer cells in vitro and in vivo. This is the first report of VES inhibition of colon cancer tumor metastases. The mechanism of VES anti-tumor and anti-metastatic activity in vivo appears to involve promotion of tumor apoptosis and inhibition of cell proliferation. These findings support further investigation of VES as a micronutrient to promote colon cancer tumor dormancy and prevent metastases. [Copyright &y& Elsevier]