γ‐Tocotrienol reversal of epithelial‐to‐mesenchymal transition in human breast cancer cells is associated with inhibition of canonical Wnt signalling

Ahmed, Rayan A.; Alawin, Osama A.; Sylvester, Paul W.

doi:10.1111/cpr.12270

Cited by 33 publications

(31 citation statements)

References 56 publications

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“…These activities were observed commonly in the concentration range of 2 to 20 µM. The molecular mechanisms reported for the antiproliferation, proapoptosis, and other anticancer activities of δ‐T3 and γ‐T3, as depicted in Figure 3, involve the inhibitory effects on WNT signaling, 116–120 NF‐κB pathway, 121–123 NOTCH signaling, 123–126 and AKT/mTOR signaling 127,128 ; and/or the activation of STAT3, 129,130 SRC kinase, 130 AMPK, 131 and receptor tyrosine kinases HER3/HER4 132,133 . The inhibition of proliferation and induction apoptosis were also reported to be mediated through tocotrienol‐induced activation of EGR‐1/BAX pathway, 134 upregulation of miR‐34a, 125 miR‐429, 135 p27/CDKN1B, 136 and PPAR‐γ, 137 disruption of lipid raft 132,133 and modification of mitochondria membrane and activation of proapoptosis genes 138–140 .…”

Section: Laboratory Studies On Ve and Cancer Preventionmentioning

confidence: 97%

“…In γ‐T3‐treated breast cancer MDA‐MB‐231 cells, cell migration machinery regulators such as RAC1 and WAVE2 signaling were reduced 153 . In addition to the reduced cell migration, γ‐T3‐treated breast cancer MDA‐MB‐231 and T‐47D cells showed epithelial‐mesenchymal transition 119 . Using the same in vitro assays, δ‐T3 was also found to suppress the migration and invasion of non‐small lung cancer cells 124 and colon cancer cells 154 .…”

Section: Laboratory Studies On Ve and Cancer Preventionmentioning

confidence: 98%

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Vitamin E and cancer prevention: Studies with different forms of tocopherols and tocotrienols

Yang

Luo

Zeng

et al. 2020

Molecular Carcinogenesis

128

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α‐Tocopherol (α‐T) is the major form of vitamin E (VE) in animals and has the highest activity in carrying out the essential antioxidant functions of VE. Because of the involvement of oxidative stress in carcinogenesis, the cancer prevention activity of α‐T has been studied extensively. Lower VE intake or nutritional status has been shown to be associated with increased cancer risk, and supplementation of α‐T to populations with VE insufficiency has shown beneficial effects in lowering the cancer risk in some intervention studies. However, several large intervention studies with α‐T conducted in North America have not demonstrated a cancer prevention effect. More recent studies have centered on the γ‐ and δ‐forms of tocopherols and tocotrienols (T3). In comparison with α‐T, these forms have much lower systemic bioavailability but have shown stronger cancer‐preventive activities in many studies in animal models and cell lines. γ‐T3 and δ‐T3 generally have even higher activities than γ‐T and δ‐T. In this article, we review recent results from human and laboratory studies on the cancer‐preventive activities of different forms of tocopherols and tocotrienols, at nutritional and pharmacological levels. We aim to elucidate the possible mechanisms of the preventive actions and discuss the possible application of the available information for human cancer prevention by different VE forms.

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Section: Laboratory Studies On Ve and Cancer Preventionmentioning

confidence: 97%

Section: Laboratory Studies On Ve and Cancer Preventionmentioning

confidence: 98%

Vitamin E and cancer prevention: Studies with different forms of tocopherols and tocotrienols

Yang

Luo

Zeng

et al. 2020

Molecular Carcinogenesis

128

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“…Both canonical and noncanonical Wnt pathways are involved in EMT of breast stem cells or cancer cells. Wnt ligands (Wnt10b/3) or receptors (FZD7/LRP6) mediate activation of the β‐catenin pathway responsible for EMT induction . In contrast, Wnt5a/5b‐induced EMT is not dependent on β‐catenin, but is involved in FZD2/STAT3 signaling .…”

Section: Wnt Signaling Induces Breast Cancer Cell Epithelial‐mesenchymentioning

confidence: 99%

Wnt signaling in human and mouse breast cancer: Focusing on Wnt ligands, receptors and antagonists

et al. 2018

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Wnt proteins, a group of secreted glycoproteins, mainly combine with receptors Frizzled (FZD) and/or low‐density‐lipoprotein receptor‐related proteins 5/6 (LRP5/6), initiating β‐catenin‐dependent and ‐independent signaling pathways. These pathways, which can be regulated by some secreted antagonists such as secreted Frizzled‐related proteins (SFRP) and dickkopf‐related protein (DKK), play a critical role in embryo development and adult homeostasis. Overactivation of Wnt signaling has been implicated in some human diseases including cancer. Wnt transgenic mice provide convincing evidence that Wnt signaling is involved in breast cancer initiation and progression, which is further strengthened by observations on human clinical breast cancer patients and studies on in vitro cultured human breast cancer cells. This review focuses on the roles of Wnt ligands, receptors and antagonists in breast cancer development instead of molecules or signaling transactivating β‐catenin independent on Wnt upstream components.

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“…Tocotrienols display potent anti-proliferative, apoptotic and autophagic effects against breast cancer cells. The anti-cancer effect of tocotrienols were found to be associated with suppression in growth factor receptor mitogenic signaling pathway and inhibition of epithelial-to-mesenchymal transition in cancer cell lines (Ahmed et al, 2016). The ability of tocotrienols to inhibit the activation and signaling of a wide variety of membrane bound receptors was recently explained (Alawin et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…The ability of tocotrienols to inhibit the activation and signaling of a wide variety of membrane bound receptors was recently explained (Alawin et al, 2016). It was found that γ-tocotrienol accumulate in and disrupt the integrity of the lipid raft domain within the plasma membrane of breast cancer cells, and this disruption of lipid raft integrity was associated with a reduction in receptor activation and signaling (Ahmed et al, 2016). Based on the plethora of data on the antitumor activity of the free tocotrienol isomers of vitamin E, it was our hypothesis that substituting the α-tocopherol isomer of vitamin E in TPGS with tocotrienols would have a higher pharmacological or antitumor activity, especially against breast and pancreatic cancer, in addition to serving as a solubilizer.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, characterization, and in-vitro antitumor activity of the polyethylene glycol (350 and 1000) succinate derivatives of the tocopherol and tocotrienol isomers of Vitamin E

Abu-Fayyad

Nazzal

2017

International Journal of Pharmaceutics

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Vitamin E refers to a group of saturated tocopherol (T) isomers and the biologically more active unsaturated tocotrienol (T3) isomers. PEGylated α-tocopherol, commercially known as Vitamin E TPGS, has been used as an emulsifier and therapeutic agent for children with vitamin E deficiency. Limited information, however, is available about the PEG conjugates of the tocotrienol isomers of vitamin E. The current work was therefore undertaken to synthesize and characterize the water soluble polyethylene glycol (PEG 350 and 1000) derivatives of T and T3. Yield and the identity of the synthesized products were confirmed by 1H NMR, mass spectroscopy, HPLC, and thermal analysis. The self-assembly of the PEGylated vitamin E isomers in water at critical micelle concentrations (CMC) was further confirmed by size, zeta, and Cryo-TEM image analysis. While stable at pH 7.4, PEG conjugates were found to rapidly hydrolyze at pH 1.2. Our data showed that PEGylated T3 isomers were significantly more active as inhibitors for P-glycoprotein than PEGylated T. The in vitro cytotoxicity of the conjugates was also tested against a large panel of normal and tumorigenic cells. Of the conjugates, γ-T3PGS 1000 and δ-T3PGS 1000 were found to have the least toxicity against non-tumorigenic breast and pancreatic cell lines, which may be advantageous for its use as functional excipients in drug delivery. The results from the current work have demonstrated the feasibility of synthesizing PEGylated conjugates of vitamin E isomers and highlighted the potential use of these conjugates in drug delivery as functional and safer excipients especially for γ-T3PGS 1000 and δ-T3PGS 1000 conjugate.

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γ‐Tocotrienol reversal of epithelial‐to‐mesenchymal transition in human breast cancer cells is associated with inhibition of canonical Wnt signalling

Abstract: γ-Tocotrienol suppression of metastatic breast cancer cell proliferation and EMT was associated with suppression of the canonical Wnt/β-catenin signalling pathway.

Cited by 33 publications

References 56 publications

Vitamin E and cancer prevention: Studies with different forms of tocopherols and tocotrienols

Vitamin E and cancer prevention: Studies with different forms of tocopherols and tocotrienols

Wnt signaling in human and mouse breast cancer: Focusing on Wnt ligands, receptors and antagonists

Synthesis, characterization, and in-vitro antitumor activity of the polyethylene glycol (350 and 1000) succinate derivatives of the tocopherol and tocotrienol isomers of Vitamin E

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