Current trends in the use of vitamin E-based micellar nanocarriers for anticancer drug delivery.

Muddineti OS, Ghosh B, Biswas S.

Expert Opin Drug Deliv. 2016 Sep 6:1-12. [Epub ahead of print]

Abstract

Owing to the complexity of cancer pathogenesis, conventional chemotherapy can be an inadequate method of killing cancer cells effectively. Nanoparticle-based drug delivery systems have been widely exploited pre-clinically in recent years. Incorporation of vitamin-E in nanocarriers have the advantage of (1) improving the hydrophobicity of the drug delivery system, thereby improving the solubility of the loaded poorly soluble anticancer drugs, (2) enhancing the biocompatibility of the polymeric drug carriers, and (3) improving the anticancer potential of the chemotherapeutic agents by reversing the cellular drug resistance via simultaneous administration. In addition to being a powerful antioxidant, vitamin E demonstrated its anticancer potential by inducing apoptosis in various cancer cell lines. Various vitamin E analogs have proven their ability to cause marked inhibition of drug efflux transporters. The review discusses the potential of incorporating vitamin E in the polymeric micelles which are designed to carry poorly water-soluble anticancer drugs. Current applications of various vitamin E-based polymeric micelles with emphasis on the use of α-tocopherol, D-α-tocopheryl succinate (α-TOS) and its conjugates such as D-α-tocopheryl polyethylene glycol-succinate (TPGS) in micellar system is delineated. Advantages of utilizing polymeric micelles for drug delivery and the challenges to treat cancer, including multiple drug resistance have been discussed.

Pathak R, Bachri A, Ghosh SP, Koturbash I, Boerma M, Binz RK, Sawyer JR, Hauer-Jensen M.

Pharm Res. 2016 Sep;33(9):2117-25. doi: 10.1007/s11095-016-1950-0.

Abstract

Ionizing radiation (IR) generates reactive oxygen species (ROS), which cause DNA double-strand breaks (DSBs) that are responsible for cytogenetic alterations. Because antioxidants are potent ROS scavengers, we determined whether the vitamin E isoform γ-tocotrienol (GT3), a radio-protective multifunctional dietary antioxidant, can suppress IR-induced cytogenetic damage. We measured DSB formation in irradiated primary human umbilical vein endothelial cells (HUVECs) by quantifying the formation of γ-H2AX foci. Chromosomal aberrations (CAs) were analyzed in irradiated HUVECs and in the bone marrow cells of irradiated mice by conventional and fluorescence-based chromosome painting techniques. Gene expression was measured in HUVECs with quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). GT3 attenuates radiation-induced cytogenetic damage, possibly by affecting RAD50 expression. GT3 should be explored as a therapeutic to reduce the risk of developing genetic diseases after radiation exposure.

Eitsuka T, Tatewaki N, Nishida H, Nakagawa K, Miyazawa T.

Int J Mol Sci. 2016 Sep 22;17(10). pii: E1605. doi: 10.3390/ijms17101605. Review.

Abstract

Tocotrienol (T3), unsaturated vitamin E, is gaining a lot of attention owing to its potent anticancer effect, since its efficacy is much greater than that of tocopherol (Toc). Various factors are known to be involved in such antitumor action, including cell cycle arrest, apoptosis induction, antiangiogenesis, anti-metastasis, nuclear factor-κB suppression, and telomerase inhibition. Owing to a difference in the affinity of T3 and Toc for the α-tocopherol transfer protein, the bioavailability of orally ingested T3 is lower than that of Toc. Furthermore, cellular uptake of T3 is interrupted by coadministration of α-Toc in vitro and in vivo. Based on this, several studies are in progress to screen for molecules that can synergize with T3 in order to augment its potency. Combinations of T3 with chemotherapeutic drugs (e.g., statins, celecoxib, and gefitinib) or dietary components (e.g., polyphenols, sesamin, and ferulic acid) exhibit synergistic actions on cancer cell growth and signaling pathways. In this review, we summarize the current status of synergistic effects of T3 and an array of agents on cancer cells, and discuss their molecular mechanisms of action. These combination strategies would encourage further investigation and application in cancer prevention and therapy.

Parnan Emamverdikhan A, Golmakani N, Tabassi SA, Hassanzadeh M, Sharifi N, Shakeri MT.

Iran J Nurs Midwifery Res. 2016 Sep-Oct;21(5):475-481.

Abstract

Menopause is associated with various complications such as depression, sleep disorders, and genitourinary atrophy. Vaginal atrophy occurs due to the loss of steroid hormones, and its major symptoms include vaginal dryness, itching, dyspareunia, and bleeding after intercourse. According to the literature, vitamin E plays a key role in estrogen stability. The aim of this study was to compare the effects of vitamin E suppositories and conjugated estrogen vaginal cream on vaginal atrophy.

In this clinical trial, 52 postmenopausal women, who were referred to a gynecology clinic in 2013, were recruited and randomly divided into two groups (26 cases per group). One group received 100 IU of vitamin E suppositories (n = 26), whereas the other group applied 0.5 g of conjugated estrogen cream for 12 weeks. Vaginal maturation value (VMV) was compared between the two groups before and after the intervention. VMV ≤ 55 was regarded as a cut-off point for vaginal atrophy. Treatment success was defined as a 10-unit increase in VMV, compared to the baseline value. Data were analyzed by Friedman test and Mann-Whitney test. P value less than 0.05 was considered statistically significant.

The mean VMV in the vitamin E group before the treatment and after 4, 8, and 12 weeks of treatment was 43.78 ± 13.75, 69.07 ± 22.75, 77.86 ± 21.79, and 80.59 ± 19.23, respectively. The corresponding values in the estrogen cream group were 42.86 ± 14.40, 86.98 ± 12.58, 92.65 ± 15, and 91.57 ± 14.10, respectively. VMV significantly improved in both the treatment groups after the intervention, compared to the preintervention period (P < 0.001). Treatment success was reported in both groups, although estrogen cream (100%) appeared to be more effective after 4 weeks of treatment, compared to vitamin E suppositories (76.9%) (P = 0.01). Based on the findings, use of vitamin E suppositories could improve the laboratory criteria for vaginal atrophy and treatment success. Therefore, vitamin E suppositories are suggested for relieving the symptoms of vaginal atrophy, especially in women who are unable to use hormone therapy or cope with the associated side effects.

Kamezaki C, Nakashima A, Yamada A, Uenishi S, Ishibashi H, Shibuya N, Hama S, Hosoi S, Yamashita E, Kogure K.

J Clin Biochem Nutr. 2016 Sep;59(2):100-106. Epub 2016 Sep 1.

Abstract

Astaxanthin and vitamin E are both effective antioxidants that are frequently used in cosmetics, as food additives, and in to prevent oxidative damage. A combination of astaxanthin and vitamin E would be expected to show an additive anntioxidative effect. In this study, liposomes co-encapsulating astaxanthin and the vitamin E derivatives α-tocopherol (α-T) or tocotrienols (T3) were prepared, and the antioxidative activity of these liposomes toward singlet oxygen and hydroxyl radical was evaluated in vitro. Liposomes co-encapsulating astaxanthin and α-T showed no additive anntioxidative effect, while the actual scavenging activity of liposomes co-encapsulating astaxanthin and T3 was higher than the calculated additive activity. To clarify why this synergistic effect occurs, the most stable structure of astaxanthin in the presence of α-T or α-T3 was calculated. Only α-T3 was predicted to form hydrogen bonding with astaxanthin, and the astaxanthin polyene chain would partially interact with the α-T3 triene chain, which could explain why there was a synergistic effect between astaxanthin and T3 but not α-T. In conclusion, co-encapsulation of astaxanthin and T3 induces synergistic scavenging activity by intermolecular interactions between the two antioxidants.

Chia LL, Jantan I, Chua KH, Lam KW, Rullah K, Aluwi MF.

Front Pharmacol. 2016 Aug 30;7:291. doi: 10.3389/fphar.2016.00291.

Abstract

Tocotrienols (T3) are well-known for their antioxidant properties besides showing therapeutic potential in clinical complications such as hyperlipidemia induced by diabetes. The aim of this study was to determine the effects of δ-T3, γ-T3, and α-T3 on insulin secretion-associated genes expression of rat pancreatic islets in a dynamic culture. Pancreatic islets freshly isolated from male Wistar rats were treated with T3 for 1 h at 37°C in a microfluidic system with continuous operation. The cells were collected for total RNA extraction and reverse-transcribed, followed by measurement of insulin secretion-associated genes expression using quantitative real-time polymerase chain reaction. Molecular docking experiments were performed to gain insights on how the T3 bind to the receptors. Short-term exposure of δ- and γ-T3 to pancreatic β cells in a stimulant glucose condition (16.7 mM) significantly regulated preproinsulin mRNA levels and insulin gene transcription. In contrast, α-T3 possessed less ability in the activation of insulin synthesis level. Essentially, potassium chloride (KCl), a β cell membrane depolarising agent added into the treatment further enhanced the insulin production. δ- and γ-T3 revealed significantly higher quantitative expression in most of the insulin secretion-associated genes groups containing 16.7 mM glucose alone and 16.7 mM glucose with 30 mM KCl ranging from 600 to 1200 μM (p < 0.05). The findings suggest the potential of δ-T3 in regulating insulin synthesis and glucose-stimulated insulin secretion through triggering pathway especially in the presence of KCl.

Strait RT, Camargo CA.

Expert Rev Respir Med. 2016 Aug;10(8):881-90. doi: 10.1080/17476348.2016.1184090.

Abstract

Asthma, a heterogeneous disease with multiple phenotypes, remains a significant health problem. Present treatments are not curative and prevention should be our ultimate goal. Vitamin E supplementation presents a potential easy and cheap preventive therapy but the results of studies are confusing and sometimes contradictory. Clarification is needed.Animal studies and research in pregnant women suggest enhanced lifetime resistance to asthma with appropriate fetal exposure to vitamin E. Vitamin E‘s preventive role is complex and includes functional variations of the different isoforms. Expert commentary: We review the most recent literature on the role of vitamin E isoforms on: lung inflammation, immune development, animal and clinical studies during pregnancy, and the potential influence of vitamin E isoforms on asthma development in offspring. We point out where data are seemingly contradictory, explain why this is so, and comment on where further clarifying research is needed and its future direction.

Chung S, Ghelfi M, Atkinson J, Parker R, Qian J, Carlin C, Manor D.

J Biol Chem. 2016 Aug 12;291(33):17028-39. doi: 10.1074/jbc.M116.734210.

Abstract

α-Tocopherol (vitamin E) is an essential nutrient for all vertebrates. From the eight naturally occurring members of the vitamin E family, α-tocopherol is the most biologically active species and is selectively retained in tissues. The hepatic α-tocopherol transfer protein (TTP) preferentially selects dietary α-tocopherol and facilitates its transport through the hepatocyte and its secretion to the circulation. In doing so, TTP regulates body-wide levels of α-tocopherol. The mechanisms by which TTP facilitates α-tocopherol trafficking in hepatocytes are poorly understood. We found that the intracellular localization of TTP in hepatocytes is dynamic and responds to the presence of α-tocopherol. In the absence of the vitamin, TTP is localized to perinuclear vesicles that harbor CD71, transferrin, and Rab8, markers of the recycling endosomes. Upon treatment with α-tocopherol, TTP- and α-tocopherol-containing vesicles translocate to the plasma membrane, prior to secretion of the vitamin to the exterior of the cells. The change in TTP localization is specific to α-tocopherol and is time- and dose-dependent. The aberrant intracellular localization patterns of lipid binding-defective TTP mutants highlight the importance of protein-lipid interaction in the transport of α-tocopherol. These findings provide the basis for a proposed mechanistic model that describes TTP-facilitated trafficking of α-tocopherol through hepatocytes.

Cuerq C, Restier L, Drai J, Blond E, Roux A, Charriere S, Michalski MC, Di Filippo M, Levy E, Lachaux A, Peretti N.

Orphanet J Rare Dis. 2016 Aug 12;11(1):114. doi: 10.1186/s13023-016-0498-8.

Abstract

Chylomicron retention disease (CMRD), a rare genetic hypocholesterolemia, results in neuro-ophtalmologic damages, which can be prevented by high doses of vitamin E during infancy. In these patients, plasma vitamin E concentration is significantly reduced due to defects of chylomicron secretion. Vitamin E in adipose tissue (AT) and red blood cells (RBC) have been proposed as potential relevant biomarkers of vitamin E status but no reference values in children are available. The objectives were (i) to establish age-reference intervals in healthy children for α-tocopherol in plasma, red blood cells (RBC) and adipose tissue (AT) and (ii) to determine the variations of α-tocopherol in patients with CMRD after oral treatment with vitamin E. Summary, this study establishes pediatric reference intervals for α-tocopherol in plasma, RBC and AT. These values will be beneficial in assessing accurate α-tocopherol status in children and to optimize the monitoring of rare diseases such as CMRD. Our data suggest that RBC α-tocopherol, appears as a relevant biomarker to appreciate the effectiveness of treatment with α-tocopherol in patients with a rare primary hypocholesterolemia. The biopsy of AT could be used at diagnosis to assess the severity of the vitamin Edeficiency and periodically after a long duration of vitamin E therapy to assess whether the treatment is effective, based on reference intervals defined in this study.

Ahmed RA, Alawin OA, Sylvester PW.

Cell Prolif. 2016 Aug;49(4):460-70. doi: 10.1111/cpr.12270.

Abstract

Frizzled-7 (FZD7) receptor-dependent activation of the canonical Wnt/β-catenin pathway plays a crucial role in epithelial-to-mesenchymal transition (EMT) and breast cancer metastasis. FZD7 and its co-receptor, low-density lipoprotein receptor-related protein 6 (LRP6), are highly expressed in MDA-MB-231 and T-47D breast cancer cells, and endogenous ligands for FZD7 include Wnt3a and Wnt5a/b. γ-Tocotrienol, a natural isoform of vitamin E, inhibits human breast cancer cell proliferation and EMT. Here, studies have been conducted to investigate the role of the canonical Wnt pathway in mediating inhibitory effects of γ-tocotrienolon EMT in human breast cancer cells. Results show γ-Tocotrienol was found to induce dose-responsive inhibition of MDA-MB-231 and T-47D cell growth at doses that had no effect on immortalized normal MCF-10A mammary epithelial cells. These growth inhibitory effects were associated with suppression in canonical Wnt signalling, reversal of EMT and significant reduction in breast cancer cell motility. In conclusion, γ-Tocotrienol suppression of metastatic breast cancer cell proliferation and EMT was associated with suppression of the canonical Wnt/β-catenin signalling pathway.