Delta-Tocotrienol Modulates Glutamine Dependence by Inhibiting ASCT2 and LAT1 Transporters in Non-Small Cell Lung Cancer (NSCLC) Cells: A Metabolomic Approach

Rajasinghe LD, Hutchings M, Gupta SV

Metabolites. 2019 Mar 13;9(3). pii: E50. doi: 10.3390/metabo9030050.

Abstract

The growth and development of non-small cell lung cancer (NSCLC) primarily depends on glutamine. Both glutamine and essential amino acids (EAAs) have been reported to upregulate mTOR in NSCLC, which is a bioenergetics sensor involved in the regulation of cell growth, cell survival, and protein synthesis. Seen as novel concepts in cancer development, ASCT2 and LAT transporters allow glutamine and EAAs to enter proliferating tumors as well as send a regulatory signal to mTOR. Blocking or downregulating these glutamine transporters in order to inhibit glutamine uptake would be an excellent therapeutic target for treatment of NSCLC. This study aimed to validate the metabolic dysregulation of glutamine and its derivatives in NSCLC using cellular 1H-NMR metabolomic approach while exploring the mechanism of delta-tocotrienol (δT) on glutamine transporters, and mTOR pathway. Cellular metabolomics analysis showed significant inhibition in the uptake of glutamine, its derivatives glutamate and glutathione, and some EAAs in both cell lines with δT treatment. Inhibition of glutamine transporters (ASCT2 and LAT1) and mTOR pathway proteins (P-mTOR and p-4EBP1) was evident in Western blot analysis in a dose-dependent manner. Our findings suggest that δT inhibits glutamine transporters, thus inhibiting glutamine uptake into proliferating cells, which results in the inhibition of cell proliferation and induction of apoptosis via downregulation of the mTOR pathway.

Thomsen CB, Andersen RF, Steffensen KD, Adimi P, Jakobsen A

Pharmacol Res. 2019 Mar;141:392-396. doi: 10.1016/j.phrs.2019.01.017. Epub 2019 Jan 9.

Abstract

Delta tocotrienol has anti-neoplastic activity as demonstrated in several in-vitro and in-vivo investigations. The effect relies on inhibition of different pathways. It also has antiangiogenic activity, and an additive effect to bevacizumab may be expected. The present study was a phase II trial of bevacizumab combined with tocotrienol in chemotherapy refractory ovarian cancer. The study also included analysis of circulating tumor specific HOXA9 methylated DNA (HOXA9 meth-ctDNA) during treatment. The study included 23 patients. The rate of disease stabilization was 70% with very low toxicity. The median PFS was 6.9 months and the median OS 10.9 months, which is rather high compared to the current literature. A division of the patients according to level of HOXA9 meth-ctDNA already after the first cycle of chemotherapy resulted in two groups of patients with different prognoses. Patients with an increasing level of HOXA9 meth-ctDNA had a median PFS and OS of 1.4 and 4.3 months, respectively, compared to 7.8 and 12 months in the group with stable or decreasing levels. The combination of bevacizumab and tocotrienol is potent in chemotherapy refractory ovarian cancer. The level of HOXA9 meth-ctDNA after one cycle of chemotherapy holds important prognostic information.

Lin JH, Chen SJ, Liu H, Yan Y, Zheng JH

Int J Vitam Nutr Res. 2019 Feb 26:1-8. doi: 10.1024/0300-9831/a000553. [Epub ahead of print]

Abstract

BACKGROUND:

Vitamin E has anti-cancer properties, which was demonstrated mainly due to its antioxidant effect. Several epidemiological studies have investigated the association between vitamin E consumption and the risk of bladder cancer. However, the results were inconsistent. The meta-analysis study aimed to evaluate the association of vitamin E consumption and the risk of bladder cancer.

METHODS:

We conducted a systematic literature search in the electronic databases, which included MEDLINE, EMBASE and the Cochrane Library till 1 January 2016. The pooled relative risk ratios (RRs) with 95% confidence intervals (CIs) were calculated depending on the heterogeneity among studies. Subgroup analysis and sensitivity analysis were also performed. Publication bias was assessed using Begg’s test and Egger’s test.

RESULTS:

A total of 11 prospective studies (3 randomized clinical trials and 8 cohort studies) including 575601 participants were identified to be eligible for our present meta-analysis. The pooled RRs with 95% CI for highest versus lowest vitamin E consumption was 0.89 (0.78-1.00). An inverse linear association between vitamin E consumption and bladder cancer risk was detected in the dose response analysis. The results were also stable in the subgroup analysis and sensitivity analysis. Meanwhile, no obvious publication bias was observed.

CONCLUSIONS:

Our study indicates that vitamin E consumption was inversely associated with the risk of bladder cancer.

Aggarwal V, Kashyap D, Sak K, Tuli HS, Jain A, Chaudhary A, Garg VK, Sethi G, Yerer MB

Int J Mol Sci. 2019 Feb 2;20(3). pii: E656. doi: 10.3390/ijms20030656.

Abstract

Tocotrienols, found in several natural sources such as rice bran, annatto seeds, and palm oil have been reported to exert various beneficial health promoting properties especially against chronic diseases, including cancer. The incidence of cancer is rapidly increasing around the world not only because of continual aging and growth in global population, but also due to the adaptation of Western lifestyle behaviours, including intake of high fat diets and low physical activity. Tocotrienols can suppress the growth of different malignancies, including those of breast, lung, ovary, prostate, liver, brain, colon, myeloma, and pancreas. These findings, together with the reported safety profile of tocotrienols in healthy human volunteers, encourage further studies on the potential application of these compounds in cancer prevention and treatment. In the current article, detailed information about the potential molecular mechanisms of actions of tocotrienols in different cancer models has been presented and the possible effects of these vitamin E analogues on various important cancer hallmarks, i.e., cellular proliferation, apoptosis, angiogenesis, metastasis, and inflammation have been briefly analyzed.

Wang J, Guo H, Lin T, Song Y, Zhang H, Wang B, Zhang Y, Li J, Huo Y, Wang X, Qin X, Xu X.

J Acad Nutr Diet. 2019 Jan 31. pii: S2212-2672(18)30852-9. doi: 10.1016/j.jand.2018.11.017. [Epub ahead of print]

Abstract

BACKGROUND:

Evidence from epidemiologic studies has been inconsistent regarding the role of vitamin E in cancer incidence risk.

OBJECTIVE:

The aim of this study was to evaluate the prospective association between baseline plasma vitamin E levels and subsequent cancer risk in Chinese adults with hypertension, and to identify effect modifiers.

DESIGN:

A nested, case-control study was conducted from 20,702 hypertensive participants in the China Stroke Primary Prevention Trial, a randomized, double-blind, controlled trial, conducted from May 2008 to August 2013.

PARTICIPANTS:

The current study included 229 new cancer cases and 229 controls matched for age (±1 year), sex, treatment group, and study site.

MAIN OUTCOME MEASURES:

Plasma vitamin E was measured by liquid chromatography with tandem quadrupole mass spectrometers and plasma selenium was measured by inductively coupled plasma mass spectrometry using Thermo Fisher iCAP Q ICP-MS.

STATISTICAL ANALYSES:

Odds ratios (OR) of cancer in relation to plasma concentrations of vitamin E were calculated using conditional logistic regression models.

RESULTS:

Median follow-up duration was 4.5 years. Overall, vitamin E was not associated with subsequent risk of total cancer (per 1-mg/L [2.3 μmol/L] increase: OR 1.01, 95% CI 0.93 to 1.09) and non-gastrointestinal cancer (OR 1.10, 95% CI 0.98 to 1.24). However, there was a significant, inverse association between vitamin E and gastrointestinal cancer (OR 0.86, 95% CI 0.75 to 0.99), particularly esophageal cancer (OR 0.67, 95% CI 0.48 to 0.95). Moreover, high vitamin E decreased the risk of total cancer (OR 0.91, 95% CI 0.84 to 0.99) and gastrointestinal cancer (OR 0.83, 95% CI 0.73 to 0.95) among patients with high selenium levels (median≥83.7 μg/L [1.1 μmol/L]), and increased the risk of total cancer (OR 1.13, 95% CI 1.00 to 1.26) and non-gastrointestinal cancer (OR 1.25, 95% CI 1.03 to 1.50) among those with low selenium levels (<83.7 μg/L [1.1 μmol/L]).

CONCLUSIONS:

This study suggests that higher levels of plasma vitamin E are associated with reduced risk of gastrointestinal cancer. High vitamin E decreased the risk of total cancer among patients with high selenium levels, but increased the risk of total cancer among those with low selenium levels.

Tham SY, Loh HS, Mai CW, Fu JY

Int J Mol Sci. 2019 Jan 16;20(2). pii: E372. doi: 10.3390/ijms20020372.

Abstract

Malignancy often arises from sophisticated defects in the intricate molecular mechanisms of cells, rendering a complicated molecular ground to effectively target cancers. Resistance toward cell death and enhancement of cell survival are the common adaptations in cancer due to its infinite proliferative capacity. Existing cancer treatment strategies that target a single molecular pathway or cancer hallmark fail to fully resolve the problem. Hence, multitargeted anticancer agents that can concurrently target cell death and survival pathways are seen as a promising alternative to treat cancer. Tocotrienols, a minor constituent of the vitamin E family that have previously been reported to induce various cell death mechanisms and target several key survival pathways, could be an effective anticancer agent. This review puts forward the potential application of tocotrienols as an anticancer treatment from a perspective of influencing the life or death decision of cancer cells. The cell death mechanisms elicited by tocotrienols, particularly apoptosis and autophagy, are highlighted. The influences of several cell survival signaling pathways in shaping cancer cell death, particularly NF-κB, PI3K/Akt, MAPK, and Wnt, are also reviewed. This review may stimulate further mechanistic researches and foster clinical applications of tocotrienols via rational drug designs.

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

Recent Pat Anticancer Drug Discov. 2019 Jan 15. doi: 10.2174/1574892814666190116111827. [Epub ahead of print]

Abstract

BACKGROUND:

Tocotrienols (TTs) are vitamin E derivatives naturally occurring in several plants and vegetable oils. Like Tocopherols (TPs), they comprise four isoforms, α, β, γ and δ, but unlike TPs, they present an unsaturated isoprenoid chain. Recent studies indicate that TTs provide important health benefits, including neuroprotective, anti-inflammatory, anti-oxidant, cholesterol lowering and immunomodulatory effects. Moreover, they have been found to possess unique anti-cancer properties.

OBJECTIVE:

The purpose of this review is to present an overview of the state of the art of TTs role in cancer prevention and treatment, as well as to describe recent patents proposing new methods for TTs isolation, chemical modification and use in cancer prevention and/or therapy.

METHODS:

Recent literature and patents focusing on TTs anti-cancer applications have been identified and reviewed, with special regard to their scientific impact and novelty.

RESULTS:

TTs have demonstrated a significant anti-cancer activity in multiple tumor types, both in vitro and in vivo. Furthermore, they have shown synergistic effects when given in combination with standard anti-cancer agents or other anti-tumor natural compounds. Finally, new purification processes and transgenic sources have been designed in order to improve TTs production, and novel TTs formulations and synthetic derivatives have been developed to enhance their solubility and bioavailability.

CONCLUSION:

The promising anti-cancer effects shown by TTs in several preclinical studies may open new opportunities of therapeutic interventions in different tumors. Thus, clinical trials aimed at confirming TTs chemopreventive and tumor-suppressing activity, particularly in combination with standard therapies, are urgently needed.

Aykin-Burns N, Pathak R, Boerma M, Kim T, Hauer-Jensen M

Semin Radiat Oncol. 2019 Jan;29(1):55-61. doi: 10.1016/j.semradonc.2018.10.008.

Abstract

Despite advances in radiation delivery techniques, side effects of radiation therapy due to radiation exposure of normal tissues are common and can limit the deliverable dose to tumors. Significant interests lie in pharmacologic modifiers that may protect against normal tissue toxicity from cancer treatment while simultaneously enhancing the tumor response to therapy. While no such treatments are available in the clinic, this is an area of active preclinical and clinical research. This review summarizes research studies that provide evidence to indicate that tocotrienols, natural forms of vitamin E, are potent radiation protectors and may also have antitumor effects. Hence, several current clinical trials test tocotrienols as concomitant treatment in cancer therapies.

Sun WG, Song RP, Wang Y, Ge S, Zhang YH, Wang HX, Liu J, Liu LX

J Agric Food Chem. 2018 Dec 18. doi: 10.1021/acs.jafc.8b05832. [Epub ahead of print]

Abstract

γ-Tocotrienol (γ-T3) exhibits the activity of anti-cancer via regulating cell signaling pathways. Nuclear factor-kB (NF-kB), one of crucial pro-inflammatory factors, involved in the regulation of cell proliferation, apoptosis, invasion and migration of tumor. In the present study, NF-kB activity inhibited by γ-T3 was investigated in gastric cancer cells. Cell proliferation, NF-kB activity, active protein phosphatase type 2A (PP2A), and ataxia-telangiectasia mutated (ATM) protein were explored using MTT, methylene blue, ELISA, malachite green, luciferase and Western blotting assays. The effects of γ-T3 on tumor growth, the expression of NF-kB and PP2A proteins were also further examined by implanting human gastric cancer cells in a BALB/c nude mouse model. The results showed that γ-T3 significantly inhibited the cell proliferation and attenuated the NF-kB activity in vitro and in vivo. γ-T3 dramatically increased PP2A activity and protein expression, which suppressed ATM phosphorylation and its translocation to the cytoplasm in gastric cancer cells. Thus, our findings may provide mechanistic insight into effects of γ-T3 on the regulation of NF-kB activity by a PP2A-dependent mechanism and suggest that PP2A may serve as a molecular target for a potential chemopreventive agent.

Khadangi F, Azzi A

IUBMB Life. 2018 Dec 14. doi: 10.1002/iub.1990. [Epub ahead of print]

Abstract

α-Tocopherol is the only tocopherol that has been shown to prevent the human deficiency disease Ataxia with Isolated Vitamin E Deficiency (AVED), and thus it is the only one that, for humans, can be called vitamin E. Vitamin E in addition to preventing AVED has documented immune boosting properties and an activity against nonalcoholic hepatosteatosis and low-grade inflammation. Epidemiological studies indicating that vitamin E could prevent cardiovascular events, neurodegenerative disease, macular degeneration, and cancer were in general not confirmed by clinical intervention studies. Vitamin E and some of its metabolites modulate cell signaling and gene transcription. Future research is needed to achieve a better understanding of the molecular events leading to gene regulation by vitamin E, especially in its phosphorylated form. Isolation and characterization of the vitamin E kinase and vitamin E phosphate phosphatase will help in the understanding of cell regulation processes modulated by vitamin E. A clarification of the pathogenesis of AVED remains an important goal to be achieved.