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 C and Vitamin E Mitigate the Risk of Pancreatic Ductal Adenocarcinoma from Meat-Derived Mutagen Exposure in Adults in a Case-Control Study

Li D, Tang H, Wei P, Zheng J, Daniel CR, Hassan MM

J Nutr. 2019 May 17. pii: nxz081. doi: 10.1093/jn/nxz081. [Epub ahead of print]

Abstract

BACKGROUND:

Previous studies have found that meat-derived mutagens increase, and vitamin C or E decrease, the risk of pancreatic cancer.

OBJECTIVE:

The aim of this study was to determine whether intake of vitamin C or E modulates the association between meat-derived mutagen exposure and risk of pancreatic cancer.

DESIGN:

We conducted a case-control study in 1321 patients with pathologically confirmed pancreatic ductal adenocarcinoma (PDAC) and 1061 healthy controls (aged 28-88 y). Cases and controls were frequency-matched by age, sex, and race/ethnicity. Mutagen intake was assessed using a meat preparation questionnaire. Intakes of vitamin C, E, and other dietary components were assessed via a food-frequency questionnaire in a subset of 811 cases and 818 controls. ORs and 95% CIs were estimated in multivariable-adjusted logistic regression models.

RESULTS:

The risk of PDAC was not associated with meat intake but was associated with consumption of well-done grilled or barbecued chicken (OR: 1.57; 95% CI: 1.18, 2.09; P = 0.001). Intake of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline was associated with increased PDAC risk (Ptrend = 0.047). Participants in the highest, as compared with the lowest, quintile of 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (PhIP) intake experienced a 38% increased risk of PDAC (95% CI: 1.00, 1.90; P = 0.048). Intakes of total vitamin C or E from food and supplements or from supplements alone were each inversely associated with PDAC risk. Stratified analyses showed differential associations for PhIP intake and PDAC risk, such that risk increased among individuals with lower intake of vitamin C or E and decreased among those with higher vitamin intake. Significant interactions of dietary vitamin C, dietary vitamin E, and total vitamin E with PhIP intake were detected (Pinteraction = 0.023, <0.001, and 0.013, respectively).

CONCLUSIONS:

Consistent with experimental evidence, this study of 811 cases and 818 controls has shown that high intake of dietary vitamin C or E mitigates the risk of PhIP-related PDAC.

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Molecular Mechanisms of Action of Tocotrienols in Cancer: Recent Trends and Advancements

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.

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Effects of alpha-tocopherol on acute pancreatitis in rat

Özgül H, Tatar C1, Özer B, Aydın H, Sarı S, Özer SP

Ulus Travma Acil Cerrahi Derg. 2019 Jan;25(1):1-6. doi: 10.5505/tjtes.2018.30413.

Abstract

BACKGROUND:

Acute pancreatitis is a disease with high morbidity and mortality, despite all the advances in technology. The overall mortality rate of acute pancreatitis is 10%, whereas the mortality rate in infected necrotizing pancreatitis is approximately 35%. In this study, we aimed to establish acute pancreatitis in rats in order to try out the alpha-tocopherol treatment protocol and to reveal the results biochemically and histopathologically.

METHODS:

Twenty-four male male Sprague-Dawley rats weighing between 300 and 350 g were used in the study. In Group 1, 80 µg/kg of normal saline was subcutaneously injected into eight rats; in Group 2, 80 µg/kg of cerulein was subcutaneously injected into eight rats; and in Group 3, 80 µg/kg of cerulein was subcutaneously injected into eight rats. In addition, 30 mg/kg of alpha-tocopherol was intraperitoneally injected into eight rats.

RESULTS:

The mean Schoenberg score, serum amylase, and lipase and Neutrophil Gelatinase-Associated Lipocalin (NGAL) levels were statistically significantly higher in Group 2 than in Group 1. The mean Schoenberg score and serum amylase and lipase levels were statistically significantly lower in Group 3 than in Group 2.

CONCLUSION:

In this experimental study rat model of cerulein-induced acute pancreatitis, 30 mg/kg of alpha-tocopherol was injected intraperitoneally to examine its effect on pancreatitis. The improvement was observed in the histopathological examination of pancreatic tissues. We think that alpha-tocopherol may have a therapeutic effect on pancreatic tissue.

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Vitamin E status and its determinants in patients with cystic fibrosis

Sapiejka E, Krzyżanowska-Jankowska P, Wenska-Chyży E, Szczepanik M, Walkowiak D, Cofta S, Pogorzelski A, Skorupa W, Walkowiak J

Adv Med Sci. 2018 Aug 3;63(2):341-346. doi: 10.1016/j.advms.2018.04.001. [Epub ahead of print]

Abstract

PURPOSE:

The risk of vitamin E deficiency is of primary concern in cystic fibrosis patients. However, early diagnosis and routine vitamin Esupplementation can lead to its normal or even high levels. In the present study, we assessed vitamin E status in a large group of cystic fibrosis patients. Moreover, we also aimed to establish determinants of its body resources in cystic fibrosis patients.

MATERIAL AND METHODS:

The study group comprised 211 cystic fibrosis patients aged from 1 month to 48 years. In all of them serum α-tocopherol concentration was analyzed using high-performance liquid chromatography.

RESULTS:

Median vitamin E concentration was 9.9 μg/ml (1st-3rd quartile: 7.5-13.5). Vitamin E deficiency was found in 17 (8.0%) and high levels were documented in 24 (11.4%) participants. Patients with and without vitamin E deficiency did not differ significantly with respect to age, standardized body weight and height, FEV1, albumin concentration and vitamin E supplementation dose. However, vitamin E deficiency appeared more frequently in participants without vitamin E supplementation. Moreover, in multiple linear regression analysis pancreatic insufficiency, severe CFTR gene mutation and vitamin E dose, were potentially defined as determinants of vitamin E concentration.

CONCLUSIONS:

Vitamin E deficiency in cystic fibrosis patients is rather rare nowadays. Excessive vitamin E levels seem to be more frequent. Vitamin E status wasn’t documented to be strictly related to clinical determinants. Beyond vitamin E supplementation, exocrine pancreatic function and CFTR gene mutations may have had an impact on the vitamin E body resources in cystic fibrosis patients.

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Gemcitabine-vitamin E conjugates: Synthesis, characterization, entrapment into nanoemulsions, and in-vitro deamination and antitumor activity.

Abu-Fayyad A, Nazzal S.

Int J Pharm. 2017 Jun 13;528(1-2):463-470. doi: 10.1016/j.ijpharm.2017.06.031. [Epub ahead of print]

bstract

Gemcitabine is the first line therapy for pancreatic cancer. It is, however, extensively metabolized to the inactive form by deamination enzymatic reaction. Conjugation of gemcitabine with fatty acids on its 4-amino group was found to protect it from deamination deactivation reaction. The objective of the present study was to test the in-vitro anticancer activity of gemcitabine conjugated to the γ-tocotrienol isomer of vitamin E against pancreatic tumor cells. This objective was based on reported studies in which it was demonstrated that free tocotrienol isomers of vitamin E can potentiate the anticancer activity of gemcitabine. To accomplish this objective, a full synthesis scheme for gemcitabine conjugation to fatty acids (stearic and linoleic) and the tocopherol and tocotrienol isomers of vitamin E (α-T and γ-T3) was presented. The conjugates were characterized by 1H NMR and mass spectrometry analysis and tested for their susceptibility to deamination. Also discussed is the impact of entrapping the conjugates into nanoemulsions on the physiochemical properties of the delivery system and the in vitro anticancer activity of gemcitabine against Bx-PC-3 and PNAC-1 pancreatic cancer cells. In-vitro enzymatic deamination study showed that the γ-T3 conjugate of gemcitabine was least affected by deamination deactivation reaction when compared with the free and conjugated gemcitabine in solution. Furthermore, in-vitro cytotoxicity study demonstrated that entrapment of gemcitabine-lipid conjugates into nanoemulsions significantly enhanced their anticancer activity when compared to the free drug. It was concluded that conjugation to the γ-T3 isomer is a viable option for gemcitabine delivery and is worthy of further investigation.

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δ-Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer metastasis.

Husain K, Centeno BA, Coppola D, Trevino J, Sebti SM, Malafa MP

Oncotarget. 2017 May 9;8(19):31554-31567. doi: 10.18632/oncotarget.15767.

Abstract

The growth, metastasis, and chemotherapy resistance of pancreatic ductal adenocarcinoma (PDAC) is characterized by the activation and growth of tumor-initiating cells in distant organs that have stem-like properties. Thus, inhibiting growth of these cells may prevent PDAC growth and metastases. We have demonstrated that δ-tocotrienol, a natural form of vitamin E (VEDT), is bioactive against cancer, delays progression, and prevents metastases in transgenic mouse models of PDAC. In this report, we provide the first evidence that VEDT selectively inhibits PDAC stem-like cells. VEDT inhibited the viability, survival, self-renewal, and expression of Oct4 and Sox2 transcription factors in 3 models of PDAC stem-like cells. In addition, VEDT inhibited the migration, invasion, and several biomarkers of epithelial-to-mesenchymal transition and angiogenesis in PDAC cells and tumors. These processes are critical for tumor metastases. Furthermore, in the L3.6pl orthotopic model of PDAC metastases, VEDT significantly inhibited growth and metastases of these cells. Finally, in an orthotopic xenograft model of human PDAC stem-like cells, we showed that VEDT significantly retarded the growth and metastases of gemcitabine-resistant PDAC human stem-like cells. Because VEDT has been shown to be safe and to reach bioactive levels in humans, this work supports investigating VEDT for chemoprevention of PDAC metastases.

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Effects of Tocotrienols on Insulin Secretion-Associated Genes Expression of Rat Pancreatic Islets in a Dynamic Culture.

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.

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Pharmacokinetics and safety of vitamin E δ-tocotrienol after single and multiple doses in healthy subjects with measurement of vitamin E metabolite

Mahipal A, Klapman J, Vignesh S, Yang CS, Neuger A, Chen DT, Malafa MP.

Cancer Chemother Pharmacol. 2016 Jul;78(1):157-65. doi: 10.1007/s00280-016-3048-0.

Abstract

Vitamin E delta-tocotrienol (VEDT) has demonstrated chemopreventive and antineoplastic activity in preclinical models. The aim of our study was to determine the safety and pharmacokinetics of VEDT and its metabolites after single- and multiple-dose administrations in healthy subjects. Our results suggest that VEDT can be safely consumed by healthy subjects and achieve bioactive levels, supporting the investigation of VEDT for chemoprevention.

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Vitamins in Pancreatic Cancer: A Review of Underlying Mechanisms and Future Applications

Davis-Yadley AH, Malafa MP.

Adv Nutr. 2015 Nov 13;6(6):774-802.

Abstract

Although there is increasing evidence that vitamins influence pancreatic adenocarcinoma biology and carcinogenesis, a comprehensive review is lacking. In this study, we performed a PubMed literature search to review the anticancer mechanisms and the preclinical and clinical studies that support the development of the bioactive vitamins A, C, D, E, and K in pancreatic cancer intervention. Preclinical studies have shown promising results for vitamin A in pancreatic cancer prevention, with clinical trials showing intriguing responses in combination with immunotherapy. For vitamin C, preclinical studies have shown slower tumor growth rates and/or increased survival when used alone or in combination with gemcitabine, with clinical trials with this combination revealing decreased primary tumor sizes and improved performance status. Preclinical studies with vitamin D analogues have shown potent antiproliferative effects and repression of migration and invasion of pancreatic cancer cells, with a clinical trial showing increased time to progression when calciferol was added to docetaxel. For vitamin E, preclinical studies have shown that δ-tocotrienol and γ-tocotrienol inhibited tumor cell growth and survival and augmented gemcitabine activity. Early-phase clinical trials with δ-tocotrienol are ongoing. Vitamin K demonstrates activation of apoptosis and inhibition of cellular growth in pancreatic tumor cells; however, there are no clinical studies available for further evaluation. Although preclinical and clinical studies are encouraging, randomized controlled trials with endpoints based on insights gained from mechanistic and preclinical studies and early-phase clinical trials are required to determine the efficacy of bioactive vitamin interventions in pancreatic cancer.

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