Vitamin E δ-tocotrienol sensitizes human pancreatic cancer cells to TRAIL-induced apoptosis through proteasome-mediated down-regulation of c-FLIPs

Francois RA, Zhang A, Husain K, Wang C, Hutchinson S, Kongnyuy M, Batra SK, Coppola D, Sebti SM, Malafa MP

Cancer Cell Int. 2019 Jul 22;19:189. doi: 10.1186/s12935-019-0876-0. eCollection 2019.

Abstract

BACKGROUND:

Vitamin E δ-tocotrienol (VEDT), a vitamin E compound isolated from sources such as palm fruit and annatto beans, has been reported to have cancer chemopreventive and therapeutic effects.

METHODS:

We report a novel function of VEDT in augmenting tumor necrosis factor-related apoptosis-inducing ligand- (TRAIL-) induced apoptosis in pancreatic cancer cells. The effects of VEDT were shown by its ability to trigger caspase-8-dependent apoptosis in pancreatic cancer cells.

RESULTS:

When combined with TRAIL, VEDT significantly augmented TRAIL-induced apoptosis of pancreatic cancer cells. VEDT decreased cellular FLICE inhibitory protein (c-FLIP) levels without consistently modulating the expression of decoy death receptors 1, 2, 3 or death receptors 4 and 5. Enforced expression of c-FLIP substantially attenuated VEDT/TRAIL-induced apoptosis. Thus, c-FLIP reduction plays an important part in mediating VEDT/TRAIL-induced apoptosis. Moreover, VEDT increased c-FLIP ubiquitination and degradation but did not affect its transcription, suggesting that VEDT decreases c-FLIP levels through promoting its degradation. Of note, degradation of c-FLIP and enhanced TRAIL-induced apoptosis in pancreatic cancer cells were observed only with the anticancer bioactive vitamin E compounds δ-, γ-, and β-tocotrienol but not with the anticancer inactive vitamin E compounds α-tocotrienol and α-, β-, γ-, and δ-tocopherol.

CONCLUSIONS:

c-FLIP degradation is a key event for death receptor-induced apoptosis by anticancer bioactive vitamin E compounds in pancreatic cancer cells. Moreover, VEDT augmented TRAIL inhibition of pancreatic tumor growth and induction of apoptosis in vivo. Combination therapy with TRAIL agonists and bioactive vitamin E compounds may offer a novel strategy for pancreatic cancer intervention.

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Vitamin E and Alzheimer’s disease: what do we know so far?

Browne D, McGuinness B, Woodside JV, McKay GJ

Clin Interv Aging. 2019 Jul 18;14:1303-1317. doi: 10.2147/CIA.S186760. eCollection 2019.

Abstract

Vitamin E has been proposed as a potential clinical intervention for Alzheimer’s disease (AD) given the plausibility of its various biological functions in influencing the neurodegenerative processes associated with the condition. The tocopherol and tocotrienol isoforms of vitamin Ehave multiple properties including potent antioxidant and anti-inflammatory characteristics, in addition to influences on immune function, cellular signalling and lowering cholesterol. Several of these roles offer a theoretical rationale for providing benefit for the treatment of AD-associated pathology. Diminished circulating concentrations of vitamin E have been demonstrated in individuals with AD. Reduced plasma levels have furthermore been associated with an increased risk of AD development while intake, particularly from dietary sources, may limit or reduce the rate of disease progression. This benefit may be linked to synergistic actions between vitamin E isoforms and other micronutrients. Nevertheless, randomised trials have found limited and inconsistent evidence of vitamin E supplementation as an effective clinical intervention. Thus, despite a strong rationale in support of a beneficial role for vitamin E for the treatment of AD, the evidence remains inconclusive. Several factors may partly explain this discrepancy and represent the difficulties of translating complex laboratory evidence and dietary interactions into clinical interventions. Methodological design limitations of existing randomised trials and restrictions to supplementation with a single vitamin E isoform may also limit the influence of effect. Moreover, several factors influence individual responsiveness to vitamin E intake and recent findings suggest variation in the underlying genetic architecture attenuates vitamin E biological availability and activity which likely contributes to the variation in clinical responsiveness and the failure of randomised trials to date. Importantly, the clinical safety of vitamin E remains controversial and warrants further investigation.

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THE SKIN BENEFITS OF VITAMIN E

If you could, you might hire an army to defend your skin against all the assaults it has to deal with day in and day out: pollution, stress, smoke and less-than-healthy foods, to name just a few. Luckily, you can think of antioxidants like vitamin E as your skin’s own battalion.

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7 Natural Ways to Combat Chapped Skin on Little Faces

Are there any ways to treat or even prevent chapped skin naturally? Of course! Over the years I’ve learned what works—and what doesn’t—for protecting little chins, cheeks, and noses from the dry winter air. Here are the best ways to prevent, and in some cases treat, irritated facial skin in winter.

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Shaping the future of palm oil

Looking into the future we know that palm oil is here to stay. Palm oil is a superior vegetable oil when done right. It brings functional benefits to markets and economic progress to producing countries, so it has the capacity to bring benefits to many.  But it is up to all of us to decide what the future for palm oil will look like. We can create a bright tomorrow when we make the right choices.

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Take palm Vitamin E tocotrienols to protect your heart

It seems that humankind has been in search of cures for heart diseases for as long as medical science existed. The phenomenon was said to have first reared its ugly head in the 1920s and 1930s, when physicians across Britain and the United States were alerted that an uncommon disease was quickly becoming a leading cause of death.

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Effect of atherosclerosis and the protective effect of the antioxidant vitamin E on the rabbit cerebellum

Elbeltagy MAF, Elkholy WB, Salman AS

Microscopy (Oxf). 2019 Jul 15. pii: dfz023. doi: 10.1093/jmicro/dfz023. [Epub ahead of print]

Abstract

BACKGROUND:

Atherosclerosis is a major cardiovascular disease and one of the commonest causes of mortality in the world. Speech, balance, fine motor control and cognition are affected by atherosclerosis of cerebellar arteries. This study investigated the protective role of vitamin E against induced atherosclerosis in the rabbit cerebellum.

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Development of α-tocopherol surface-modified targeted delivery of 5-fluorouracil-loaded poly-D, L-lactic-co-glycolic acid nanoparticles against oral squamous cell carcinoma

Srivastava S, Gupta S, Mohammad S, Ahmad I

J Cancer Res Ther. 2019 Jul-Sep;15(3):480-490. doi: 10.4103/jcrt.JCRT_263_18.

Abstract

OBJECTIVE:

The aim of the study to develop surface modified targeted moiety α-tocopherol (α-t) encapsulated with 5-fluorouracil (5-FU)-poly-D, L-lactic-co-glycolic acid nanoparticles (PLGA NPs) toward the anticancer activity against oral squamous cell carcinoma (OSCC).

MATERIALS AND METHODS:

5-FU was conjugated with the polymer, PLGA by ionic cross-linking and α-tocopherol use as a functionalized surface moiety. Characterization, drug entrapment efficiency, and in-vitro drug release system were optimized at different pH 7.4 and pH 4.5. The in-vitro cell was performed to optimize the anticancer activity through MTT assay and apoptotic staining assay was also performed by flow cytometry to evaluate the cellular apoptotic activity and cellular uptake.

RESULTS:

The particle size was distributed within an average range of 145-162 nm, the polydispersity index values lie 0.16-0.30, and the surface charge was at the negative side, -17mV to -23mV. The in vitro drug release system showed more sympathetic situation at pH 7.4 as compared to pH 4.5, for targeted NPs, approximately 86% and 69%, respectively. The non-targeted 5-FU-PLGA NPs showed drug release of 83% and 64% at pH 7.4 and 4.5 subsequently. In vitro anticancer activity confirmed the intense inhibition by α-t-FU-PLGA NPs of 79.98% after 96 h treatment of SCC15 cells and confirmed the steady-state inhibition of 83.74% after 160 h incubation in comparison to 5-FU-PLGA NPs. Subsequently, the early apoptosis, 27.98%, and 16.45%, and late apoptosis, 47.29%, and 32.57%, suggested the higher apoptosis rate in targeted NPs against OSCC.

CONCLUSIONS:

The surface modified α-t-FU-PLGA NP was treated over SCC15 cells, and the oral cancer cells have shown the high intensity of cellular uptake, which confirmed that the target moiety has successfully invaded over the surface of cancer cells and shown advanced targeted delivery against OSCC.

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Tocotrienols and Cancer: From the State of the Art to Promising Novel Patents

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

Recent Pat Anticancer Drug Discov. 2019;14(1):5-18. doi: 10.2174/1574892814666190116111827.

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 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 for 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.

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A Redox-Inactive Derivative of Tocotrienol Suppresses Tumor Growth of Mesothelioma Cells in a Xenograft Model

Sato A, Arai T, Fusegi M, Ando A, Yano T

Biol Pharm Bull. 2019;42(6):1034-1037. doi: 10.1248/bpb.b18-00924.

Abstract

Malignant mesothelioma (MM) is an aggressive cancer with poor prognosis. We focused on the anticancer activity of tocotrienol (T3) and have reported that a new redox-inactive T3 derivative (6-O-carboxypropyl-α-tocotrienol; T3E) exerts stronger inhibitory effects on MM cell growth than that of T3 in vitro. Furthermore, we have revealed some mechanisms of T3E that are involved in anti-MM effects. However, the effect of T3E in vivo remains unclear. In this study, we compared the plasma concentrations of T3E to that of T3 using mice to clarify differences in pharmacokinetics. Blood was sequentially collected after oral administration of T3 or T3E, and plasma concentrations were analyzed by HPLC. The area under the plasma T3 and T3E concentration-time curve from 0 to 24 h (AUC0-24 h) of T3E was two times higher than that of T3. In addition, we evaluated the effect of T3E oral administration on tumor growth using a xenograft model of mice that were transplanted with human MM cells (H2052 cell line). Tumor volume was significantly reduced without body weight loss in mice orally administered 150 mg/kg T3E once per 2 d for 10 d, which suggests that T3E has potential anti-MM effects.

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