Natural forms of vitamin E and metabolites-regulation of cancer cell death and underlying mechanisms

Jiang Q

IUBMB Life. 2018 Dec 11. doi: 10.1002/iub.1978. [Epub ahead of print]

Abstract

The disappointing results from large clinical studies of α-tocopherol (αT), the major form of vitamin E in tissues, for prevention of chronic diseases including cancer have cast doubt on not only αT but also other forms of vitamin E regarding their role in preventing carcinogenesis. However, basic research has shown that specific forms of vitamin E such as γ-tocopherol (γT), δ-tocopherol (δT), γ-tocotrienol (γTE) and δ-tocotrienol (δTE) can inhibit the growth and induce death of many types of cancer cells, and are capable of suppressing cancer development in preclinical cancer models. For these activities, these vitamin E forms are much stronger than αT. Further, recent research revealed novel anti-inflammatory and anticancer effects of vitamin E metabolites including 13′-carboxychromanols. This review focuses on anti-proliferation and induction of death in cancer cells by vitamin E forms and metabolites, and discuss mechanisms underlying these anticancer activities. The existing in vitro and in vivo evidence indicates that γT, δT, tocotrienols and 13′-carboxychromanols have anti-cancer activities via modulating key signaling or mediators that regulate cell death and tumor progression, such as eicosanoids, NF-κB, STAT3, PI3K, and sphingolipid metabolism. These results provide useful scientific rationales and mechanistic understanding for further translation of basic discoveries to the clinic with respect to potential use of these vitamin E forms and metabolites for cancer prevention and therapy.

Shvachko LP, Zavelevich MP, Gluzman DF, Kravchuk IV, Telegeev GD

Exp Oncol. 2018 Dec;40(4):328-331.

Abstract

BACKGROUND:

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder associated with the activity of BCR-ABL fusion oncogene. Tyrosine kinase inhibitors are the current treatment of CML, but secondary mutations finally contribute to therapy resistance and blast crisis of the disease. The search for the novel compounds for the effective control of CML is now in the spotlight. The progression of CML to blast crisis is correlated with down-modulation of C/EBP alpha. Therefore, C/EBP alpha may be considered as a putative target in differentiation therapies in myeloid leukemias. The aim of the study was to assess the potential of vitamin E as the possible inducer of C/EBP alpha expression in BCR-ABL-positive CML K562 cells.

MATERIALS AND METHODS:

RNA extracted from K562 cells cultured with valproic acid or vitamin E was converted to cDNA, RT-PCR reactions were carried out using HotStarTaq DNA polymerase with primers for C/EBP alpha and granulocyte colony-stimulating factor receptor (G-CSFR).

RESULTS:

We have not found detectable expression of C/EBP alpha in K562 cells. Upon 48-h culture with vitamin E at a dose of 100 µM, K562 cells expressed both C/EBP alpha and G-CSFR.

CONCLUSION:

Vitamin E restored the expression of C/EBP alpha mRNA in chronic myelogenous leukemia K562 cells. In this setting, G-CSFR expression in vitamin E treated K562 cells seems to suggest the activation to granulocytic differentiation. It should be further elucidated whether such effects of vitamin E on C/EBP alpha transcription factor are direct or mediated indirectly due to antioxidant properties of vitamin E.

Maniam G, Mai CW, Zulkefeli M, Dufès C, Tan DM, Fu JY

Front Pharmacol. 2018 Nov 26;9:1358. doi: 10.3389/fphar.2018.01358. eCollection 2018.

Abstract

Plant-derived phytonutrients have emerged as health enhancers. Tocotrienols from the vitamin E family gained high attention in recent years due to their multi-targeted biological properties, including lipid-lowering, neuroprotection, anti-inflammatory, antioxidant, and anticancer effects. Despite well-defined mechanism of action as an anti-cancer agent, their clinical use is hampered by poor pharmacokinetic profile and low oral bioavailability. Delivery systems based on nanotechnology were proven to be advantageous in elevating the delivery of tocotrienolsto tumor sites for enhanced efficacy. To date, preclinical development of nanocarriers for tocotrienols include niosomes, lipid nanoemulsions, nanostructured lipid carriers (NLCs) and polymeric nanoparticles. Active targeting was explored via the use of transferrin as targeting ligand in niosomes. In vitro, nanocarriers were shown to enhance the anti-proliferative efficacy and cellular uptake of tocotrienols in cancer cells. In vivo, improved bioavailability of tocotrienols were reported with NLCs while marked tumor regression was observed with transferrin-targeted niosomes. In this review, the advantages and limitations of each nanocarriers were critically analyzed. Furthermore, a number of key challenges were identified including scale-up production, biological barriers, and toxicity profiles. To overcome these challenges, three research opportunities were highlighted based on rapid advancements in the field of nanomedicine. This review aims to provide a wholesome perspective for tocotrienol nanoformulations in cancer therapy directed toward effective clinical translation.

Bhori M, Singh K, Marar T, Chilakapati MK

J Biophotonics. 2018 Sep;11(9):e201800104. doi: 10.1002/jbio.201800104. Epub 2018 Jun 8.

Abstract

Many oncologists contend that patient undergoing chemotherapy must avoid antioxidant supplementation as it may interfere with the activity of the drug. In the present investigation, we have explored the influence of vitamin E, a well-known antioxidant on Camptothecin (CPT), a potent anti-cancer drug induced cell apoptosis and death of cervical cancer cells. HeLa cells were treated with different concentrations of CPT in presence and absence of 100 μm vitamin E. Treated cells were subjected to cytotoxicity studies, catalase assay, DNA fragmentation assay, clonogenic assay and flow cytometry based apoptosis detection. Also, Raman spectroscopy a label free technique which provides global information, in conjunction with multivariate tools like PCA, PCLDA and FDA, was investigated to explore vitamin E supplementation induced alterations. Our data based on biochemical and biophysical experimental analysis reveals that CPT causes DNA damage along with protein and lipid alteration culminating in cell death. Importantly, Raman spectroscopic analysis could uniquely differentiate the cluster of control and vitamin E control from CPT and CPT + Vit E treated cells. We conclusively prove that presence of vitamin E at 100 μM concentration shows promising antioxidant activity and displays no modulatory role on CPT induced effect, thereby causing no possible hindrance with the efficacy of the drug. Vitamin E may prove beneficial to alleviate chemotherapy associated side effects in patients during clinical settings which may open the doors further for subsequent exploration in in vivo preclinical studies.

Kawai M, Nakamura T, Miura N, Maeta M, Tanaka H, Ueda K, Higashi K, Moribe K, Tange K, Nakai Y, Yoshioka H, Harashima H, Akita H

Nanomedicine. 2018 Aug 28. pii: S1549-9634(18)30510-0. doi: 10.1016/j.nano.2018.08.006. [Epub ahead of print

Abstract

Cytoplasmic DNA triggers cellular immunity via activating the stimulator of interferon genes pathway. Since DNA is degradable and membrane impermeable, delivery system would permit cytoplasmic delivery by destabilizing the endosomal membrane for the use as an adjuvant. Herein, we report on the development of a plasmid DNA (pDNA)-encapsulating lipid nanoparticle (LNP). The structural components include an SS-cleavable and pH-activated lipid-like material that mounts vitamin E as a hydrophobic scaffold, and dual sensing motifs that are responsive to the intracellular environment (ssPalmE). The pDNA-encapsulating LNP (ssPalmE-LNP) induced a high interferon-β production in Raw 264.7 cells. The subcutaneous injection of ssPalmE-LNP strongly enhanced antigen-specific cytotoxic T cell activity. The ssPalmE-LNP treatment efficiently induced antitumor effects against E.G7-OVA tumor and B16-F10 melanoma metastasis. Furthermore, when combined with an anti-programmed death 1 antibody, an extensive therapeutic antitumor effect was observed. Therefore, the ssPalmE-LNP is a promising carrier of adjuvants for cancer immunotherapy.

Shanmugapriya K, Kim H, Saravana PS, Chun BS, Kang HW

Colloids Surf B Biointerfaces. 2018 Aug 20;172:170-179. doi: 10.1016/j.colsurfb.2018.08.042. [Epub ahead of print]

Abstract

Emulsion-based delivery systems have been fabricated and developed to increase the bioavailability of astaxanthin and alpha-tocopherol as active compounds for various biomedical applications. Astaxanthin-alpha tocopherol nanoemulsion (ATNE) is well known for its potential 6.-6.30 effect. The current study investigated ATNE by spontaneous (SENE) and ultrasonication emulsification (USNE) methods to optimally fabricate oil/water nanoemulsion characterized for biomedical applications. The two methods were compared by using a response surface method of 3-level Box-Behnken design (BBD) with significant factors. Transmission electron microscopy (TEM) confirmed spherical-shaped nanoemulsion from SENE and USNE methods and dynamic light scattering (DLS) proved the good stability of the fabricated nanoemulsion. Cytotoxicity studies on three different cancer cells confirmed that the nanoemulsion at higher concentrations was more toxic than one at lower concentrations by accompanying a significant decrease in the cellular viability after 24 and 48 h of exposure. The wound-healing potential using scratch assay evidenced faster healing effect of the nanoemulsion. Both minimal inhibitory concentration (MIC) and minimum bactericidal concentrations (MBC) methods confirmed significant antibacterial activity to disrupt the integrity of the bacterial cell membrane. The current results suggested that ATNE act as effectively targeted drug delivery vehicles in the future for cancer treatment applications due to its significant results of anticancer, wound healing, and antimicrobial effects.

Zhang YH, Ma K, Liu JR, Wang HX, Tian WX, Tu YH, Sun WG

Oncol Rep. 2018 Aug;40(2):999-1007. doi: 10.3892/or.2018.6497. Epub 2018 Jun 14.

Abstract

γ-tocotrienol (γ-T3), a tocotrienol isoform belonging to the vitamin E family, has been revealed to exert inhibitory effects on proliferation, migration and invasion in human gastric cancer cells. However, its precise mechanism of action is still unclear and needs to be further tested. Cyclooxygenase-2 (COX-2) is well known for its key role in promoting the migration and invasion abilities of human gastric cancer cells. In light of these data, our study aimed to validate whether the inhibitory actions of γ-T3 could be achieved by downregulation of COX-2 activity in vitro. In the present study, a Cell Counting Kit-8 (CCK-8) assay was performed to observe proliferation in human gastric cancer cells (SGC-7901 and MGC-803 cells), and wound healing and Transwell chamber assays were performed to detect migration and invasion. Western blot analyses were performed to analyse the relative expression of COX-2, matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) proteins, and enzyme-linked immunosorbent assays (ELISA) were used to determine the exocrine roles of MMP-2 and MMP-9. The results revealed that γ-T3 exerted significant inhibitory effects on proliferation, migration, invasion and COX-2 protein expression, as well as on exocrine functions of MMP-2 and MMP-9 in SGC-7901 and MGC-803 cells. Therefore, our results indicated that γ-T3 exerts inhibitory effects on migration and invasion, which may be mediated through downregulation of COX-2 expression in SGC-7901 and MGC-803 cells.

Rajasinghe LD, Pindiprolu RH, Gupta SV

Send to Onco Targets Ther. 2018 Jul 24;11:4301-4314. doi: 10.2147/OTT.S160163. eCollection 2018.

Abstract

BACKGROUND:

Delta-tocotrienol (δT), an isomer of vitamin E, exhibits anticancer properties in different cancer types including non-small-cell lung cancer (NSCLC). Yet, anti-invasive effects of δT and its underlying cellular mechanism in NSCLC have not been fully explored. Matrix metalloproteinase 9 (MMP-9)-based cell migration and invasion are critical cellular mechanisms in cancer development. The current evidence indicates that MMP-9 is upregulated in most patients, and the inhibition of MMPs is involved in decreasing invasion and metastasis in NSCLC. Therefore, its suppression is a promising strategy for attenuating cell invasion and metastasis processes in NSCLC.

PURPOSE:

The aim of this study was to evaluate the possibility of MMP-9 inhibition as the underlying mechanism behind the antimetastatic properties of δT on NSCLC cells.

METHODS:

The effects of δT on cell proliferation, migration, invasion, adhesion, and aggregation capabilities were investigated using different cell-based assays. An inhibitory effect of MMP-9 enzyme activity with δT was also identified using gel zymography. Using real-time PCR and Western blot analysis, a number of cellular proteins, regulatory genes, and miRNA involved in the Notch-1 and urokinase-type plasminogen activator (uPA)-mediated MMP-9 pathways were examined.

RESULTS:

The study found that δT inhibited cell proliferation, cell migration, invasion, aggregation, and adhesion in a concentration-dependent manner and reduced MMP-9 activities. Real-time PCR and Western blot analysis data revealed that δT increased miR-451 expressions and downregulated Notch-1-mediated nuclear factor-κB (NF-κB), which led to the repressed expression of MMP-9 and uPA proteins.

CONCLUSION:

δT attenuated tumor invasion and metastasis by the repression of MMP-9/uPA via downregulation of Notch-1 and NF-κB pathways and upregulation of miR-451. The data suggest that δT may have potential therapeutic benefit against NSCLC metastasis.

Montagnani Marelli M, Marzagalli M, Fontana F, Raimondi M, Moretti RM, Limonta P

J Cell Physiol. 2018 Aug 1. doi: 10.1002/jcp.27075. [Epub ahead of print]

Abstract

Vitamin E is composed of two groups of compounds: α-, β-, γ-, and δ-tocopherols (TPs), and the corresponding unsaturated tocotrienols(TTs). TTs are found in natural sources such as red palm oil, annatto seeds, and rice bran. In the last decades, TTs (specifically, γ-TT and δ-TT) have gained interest due to their health benefits in chronic diseases, based on their antioxidant, neuroprotective, cholesterol-lowering, anti-inflammatory activities. Several in vitro and in vivo studies pointed out that TTs also exert a significant antitumor activity in a wide range of cancer cells. Specifically, TTs were shown to exert antiproliferative/proapoptotic effects and to reduce the metastatic or angiogenic properties of different cancer cells; moreover, these compounds were reported to specifically target the subpopulation of cancer stem cells, known to be deeply involved in the development of resistance to standard therapies. Interestingly, recent studies pointed out that TTs exert a synergistic antitumor effect on cancer cells when given in combination with either standard antitumor agents (i.e., chemotherapeutics, statins, “targeted” therapies) or natural compounds with anticancer activity (i.e., sesamin, epigallocatechin gallate (EGCG), resveratrol, ferulic acid). Based on these observations, different TT synthetic derivatives and formulations were recently developed and demonstrated to improve TT water solubility and to reduce TT metabolism in cancer cells, thus increasing their biological activity. These promising results, together with the safety of TT administration in healthy subjects, suggest that these compounds might represent a new chemopreventive or anticancer treatment (i.e., in combination with standard therapies) strategy. Clinical trials aimed at confirming this antitumor activity of TTs are needed.

Cui L, Li L, Tian Y, Xu F, Qiao T

Send to Nutrients. 2018 Jun 21;10(7). pii: E801. doi: 10.3390/nu10070801.

Abstract

Epidemiological studies have provided ambiguous evidence on the association between vitamin E and esophageal cancer risk. To resolve this controversy, we performed this meta-analysis. The literature was searched by using Excerpta Medica Database (EMBASE), PubMed, the Web of Science, and the Cochrane Library from the inception to April 2018. A random effect model was utilized to calculate the odds ratio (OR) with the 95% confidence interval (95% CI). Twelve articles reporting 14 studies involving 3013 cases and 11,384 non-cases were included. By comparing the highest category with the lowest category of dietary vitamin E intake, we found that dietary vitamin E intake was inversely related to esophageal cancer risk (OR = 0.47, 95% CI: 0.36⁻0.60). Subgroup analysis revealed that dietary vitamin E intake had a significantly negative association with both the esophageal squamous cell carcinoma risk (OR = 0.29, 95% CI: 0.18⁻0.44) and the esophageal adenocarcinoma risk (OR = 0.66, 95% CI: 0.49⁻0.88). No study significantly affected the findings in the sensitivity analysis. Publication bias was discovered, however, the OR (95% CI) remained unchanged after the trim-and-fill analysis. This meta-analysis showed that the higher dietary vitamin E intake is associated with a lower esophageal cancer risk. However, the association still needs to be upheld by more large-scaled randomized controlled trials and prospective studies.