Antiproliferative effects of γ-tocotrienol are associated with lipid raft disruption in HER2-positive human breast cancer cells.

Alawin OA, Ahmed RA, Ibrahim BA, Briski KP, Sylvester PW.

J Nutr Biochem. 2016 Jan;27:266-77. doi: 10.1016/j.jnutbio.2015.09.018.

Abstract

A large percentage of human breast cancers are characterized by excessive or aberrant HER2 activity. Lipid rafts are specialized microdomains within the plasma membrane that are required for HER2 activation and signal transduction. Since the anticancer activity of γ-tocotrienol is associated with suppression in HER2 signaling, studies were conducted to examine the effects of γ-tocotrienol on HER2 activation within the lipid raft microdomain in HER2-positive SKBR3 and BT474 human breast cancer cells. Treatment with 0-5μM γ-tocotrienol induced a significant dose-dependent inhibition in cancer cell growth after a 5-day culture period, and these growth inhibitory effects were associated with a reduction in HER2 dimerization and phosphorylation (activation). Phosphorylated HER2 was found to be primarily located in the lipid raft microdomain of the plasma membrane in vehicle-treated control groups, whereas γ-tocotrienol treatment significantly inhibited this effect. Assay of plasma membrane subcellular fractions showed that γ-tocotrienol also accumulates exclusively within the lipid raft microdomain. Hydroxypropyl-β-cyclodextrin (HPβCD) is an agent that disrupts lipid raft integrity. Acute exposure to 3mM HPβCD alone had no effect, whereas an acute 24-h exposure to 20μM γ-tocotrienol alone significantly decreased SKBR3 and BT474 cell viability. However, combined treatment with these agents greatly reduced γ-tocotrienolaccumulation in the lipid raft microdomain and cytotoxicity. In summary, these findings demonstrate that the anticancer effects of γ-tocotrienol are associated with its accumulation in the lipid raft microdomain and subsequent interference with HER2 dimerization and activation in SKBR3 and BT474 human breast cancer cells.

Koufaki M.

Expert Opin Ther Pat. 2016;26(1):35-47. doi: 10.1517/13543776.2016.1106476. Review.

Abstract

The vitamin E family consists of four tocopherols and four tocotrienols. α-Tocopherol is the most studied member of this family for its antioxidant and non-antioxidant properties, while tocotrienols have attracted recent research interest. The structural motifs of the vitamin E family and specifically the chroman moiety, are amenable to various modifications in order to improve their bioactivities towards numerous therapeutic targets. This review includes the patent literature from 2010 – 2015 related to vitamin E derivatives and it is focused on 2-, 5- or 6-substituted chroman analogues. The patent search was performed using Reaxys® and esp@cenet. The chroman moiety of vitamin E is a privileged structure and an essential pharmacophore which inspired organic chemists to synthesize new analogues with improved bioactivities. Modifications at the 2- and 5- positions of the chroman ring resulted in very interesting active compounds in cellular and animal models of diseases related to oxidative stress. More recent publications and patents reported 6-substituted chromans as anticancer agents in vitro and in vivo. Additionally, an emerging interest is observed towards the use of vitamin E analogues incorporated in drug delivery systems and for medical imaging as contrast agents or fluorescent probes.

Nakaso K, Horikoshi Y, Takahashi T, Hanaki T, Nakasone M, Kitagawa Y, Koike T, Matsura T.

Neurosci Lett. 2016 Jan 1;610:117-22. doi: 10.1016/j.neulet.2015.10.062.

Abstract

Neuroprotection following signal transduction has been investigated recently as a strategy for Parkinson’s disease (PD) therapy. While oxidative stress is important in the pathogenesis of PD, neuroprotection using antioxidants such as α-tocopherol have not been successful. δ-tocotrienol (δT3), a member of the vitamin E family, has received attention because of activities other than its antioxidative effects. In the present study, we examined the estrogen receptor-β (ERβ)-mediated neuroprotective effects of δT3 in a mouse model of PD. ERβ is expressed in neuronal cells, including dopaminergic neurons in the substantia nigra. Daily forced oral administration of δT3 inhibited the loss of dopaminergic neurons in the substantia nigra. In addition, the ER inhibitor tamoxifen canceled the neuroprotective effects of δT3. Moreover, δT3 administration improved the performance of the PD mice in the wheel running activity, while tamoxifen inhibited this improved performance. These results suggest that the oral administration of δT3 may be useful in the treatment of PD patients, and ERβ may be a candidate target for the neuroprotection activity of δT3.

Kim Y, Wang W, Okla M, Kang I, Moreau R, Chung S.

J Lipid Res. 2016 Jan;57(1):66-76. doi: 10.1194/jlr.M062828.

Abstract

The Nod-like receptor 3 (NLRP3) inflammasome is an intracellular sensor that sets off the innate immune system in response to microbial-derived and endogenous metabolic danger signals. We previously reported that γ-tocotrienol (γT3) attenuated adipose tissue inflammation and insulin resistance in diet-induced obesity, but the underlying mechanism remained elusive. Here, we investigated the effects of γT3 on NLRP3 inflammasome activation and attendant consequences on type 2 diabetes. γT3 repressed inflammasome activation, caspase-1 cleavage, and interleukin (IL) 1β secretion in murine macrophages, implicating the inhibition of NLRP3 inflammasome in the anti-inflammatory and antipyroptotic properties of γT3. Furthermore, supplementation of leptin-receptor KO mice with γT3 attenuated immune cell infiltration into adipose tissue, decreased circulating IL-18 levels, preserved pancreatic β-cells, and improved insulin sensitivity. Mechanistically, γT3 regulated the NLRP3 inflammasome via a two-pronged mechanism: 1) the induction of A20/TNF-α interacting protein 3 leading to the inhibition of the TNF receptor-associated factor 6/nuclear factor κB pathway and 2) the activation of AMP-activated protein kinase/autophagy axis leading to the attenuation of caspase-1 cleavage. Collectively, we demonstrated, for the first time, that γT3 inhibits the NLRP3 inflammasome thereby delaying the progression of type 2 diabetes. This study also provides an insight into the novel therapeutic values of γT3 for treating NLRP3 inflammasome-associated chronic diseases.

Peh HY, Daniel Tan WS, Liao W, Fred Wong WS.

Pharmacol Ther. 2015 Dec 16. pii: S0163-7258(15)00229-6

Abstract

The discovery of vitamin E (α-tocopherol) began in 1922 as a vital component required in reproduction. Today, there are eight naturally occurring vitamin E isoforms, namely α-, β-, γ- and δ-tocopherol and α-, β-, γ- and δ-tocotrienol. Vitamin E are potent antioxidants, capable of neutralizing free radicals directly by donating hydrogen from its chromanol ring. α-Tocopherol is regarded the dominant form in vitamin E as the α-tocopherol transfer protein in the liver binds mainly α-tocopherol, thus preventing its degradation. That contributed to the oversight of tocotrienols and resulted in less than 3% of all vitamin E publications studying tocotrienols. Nevertheless, tocotrienols have been shown to possess superior antioxidant and anti-inflammatory properties over α-tocopherol. In particular, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase to lower cholesterol, attenuating inflammation via downregulation of transcription factor NF-κB activation, and potent radioprotectant against radiation damage are some properties unique to tocotrienols, not tocopherols. Aside from cancer, vitamin E has also been shown protective in bone, cardiovascular, eye, nephrological and neurological diseases. In light of the different pharmacological properties of tocopherols and tocotrienols, it becomes critical to specify which vitamin E isoform(s) are being studied in any future vitamin E publications. This review provides an update on vitamin E therapeutic potentials, protective effects and modes of action beyond cancer, with comparison of tocopherols against tocotrienols. With the concerted efforts in synthesizing novel vitamin E analogues and clinical pharmacology of vitamin E, it is likely that certain vitamin E isoform(s) will be therapeutic agents against human diseases besides cancer.

Wang C, Ju H, Shen C, Tong Z

Int J Clin Exp Med. 2015 Sep 15;8(9):15648-56.

Abstract

Vitamin E δ-tocotrienol has been reported to possess anticancer activity both in vitro and in vivo. However, the underlying molecular mechanisms of δ-tocotrienol induced apoptosis in triple-negative breast cancer are not fully understood. Here, we reported that microRNA-429 (miR-429) is up-regulated in two TNBC cell lines (MDA-MB-231 and MDA-MB-468), treated with δ-tocotrienol. Inhibition of miR-429 may partially rescue the apoptosis induced by δ-tocotrienol in MDA-MB-231 cells. We also showed that the forced expression of miR-429 was sufficient to lead to apoptosis in MDA-MB-231 cells. Furthermore, we identified X-linked inhibitor of apoptosis protein (XIAP) as one of miR-429’s target genes. These results suggest that the activation of miR-429 by δ-tocotrienol may be an effective approach for the prevention and treatment of triple-negative breast cancer.

Kim Y, Wang W, Okla M, Kang I, Moreau , Chung S.

J Lipid Res. 2015 Dec 1

Abstract

The Nod-like receptor 3 (NLRP3) inflammasome is an intracellular sensor that sets off the innate immune system in response to microbial-derived and endogenous metabolic danger signals. We previously reported that gamma-tocotrienol (γT3) attenuated adipose tissue inflammation and insulin resistance in diet-induced obesity, but the underlying mechanism remained elusive. Here, we investigated the effects of γT3 on NLRP3 inflammasome activation and attendant consequences on type 2 diabetes. γT3 repressed inflammasome activation, caspase-1 cleavage, and IL-1β secretion in murine macrophages, implicating the inhibition of NLRP3 inflammasome in the anti-inflammatory and anti-pyroptotic properties of γT3. Furthermore, supplementation of leptin-receptor KO mice with γT3 attenuated immune cell infiltration into adipose tissue, decreased circulating IL-18 levels, preserved pancreatic β-cells, and improved insulin sensitivity. Mechanistically, γT3 regulated the NLRP3 inflammasome via a two-pronged mechanism; 1) the induction of A20/TNFAIP3 leading to the inhibition of the TRAF6/NF-κB pathway, and 2) the activation of AMPK/autophagy axis leading to the attenuation of caspase-1 cleavage. Collectively, we demonstrated, for the first time, that γT3 inhibits the NLRP3 inflammasome thereby delaying the progression of type 2 diabetes. This study also provides an insight into the novel therapeutic values of γT3 for treating NLRP3 inflammasome-associated chronic diseases.

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.

Nakaso K, Horikoshi Y, Takahashi T, Hanaki T, Nakasone M, Kitagawa Y, Koike T, Matsura T.

Neurosci Lett. 2016 Jan 1;610:117-22.

Abstract

Neuroprotection following signal transduction has been investigated recently as a strategy for Parkinson’s disease (PD) therapy. While oxidative stress is important in the pathogenesis of PD, neuroprotection using antioxidants such as α-tocopherol have not been successful. δ-tocotrienol(δT3), a member of the vitamin E family, has received attention because of activities other than its antioxidative effects. In the present study, we examined the estrogen receptor-β (ERβ)-mediated neuroprotective effects of δT3 in a mouse model of PD. ERβ is expressed in neuronal cells, including dopaminergic neurons in the substantia nigra. Daily forced oral administration of δT3 inhibited the loss of dopaminergic neurons in the substantia nigra. In addition, the ER inhibitor tamoxifen canceled the neuroprotective effects of δT3. Moreover, δT3 administration improved the performance of the PD mice in the wheel running activity, while tamoxifen inhibited this improved performance. These results suggest that the oral administration of δT3 may be useful in the treatment of PD patients, and ERβ may be a candidate target for the neuroprotection activity of δT3.

Koufaki M.

Expert Opin Ther Pat. 2015 Oct 29:1-13

Abstract

INTRODUCTION:

The vitamin E family consists of four tocopherols and four tocotrienols. α-Tocopherol is the most studied member of this family for its antioxidant and non-antioxidant properties, while tocotrienols have attracted recent research interest. The structural motifs of the vitamin E family and specifically the chroman moiety, are amenable to various modifications in order to improve their bioactivities towards numerous therapeutic targets. Areas covered: This review includes the patent literature from 2010 – 2015 related to vitamin E derivatives and it is focused on 2-, 5- or 6-substituted chroman analogues. The patent search was performed using Reaxys® and esp@cenet. Expert opinion: The chroman moiety of vitamin E is a privileged structure and an essential pharmacophore which inspired organic chemists to synthesize new analogues with improved bioactivities. Modifications at the 2- and 5- positions of the chroman ring resulted in very interesting active compounds in cellular and animal models of diseases related to oxidative stress. More recent publications and patents reported 6-substituted chromans as anticancer agents in vitro and in vivo. Additionally, an emerging interest is observed towards the use of vitamin E analogues incorporated in drug delivery systems and for medical imaging as contrast agents or fluorescent probes.