Tocotrienols as an Anti-Breast Cancer Agent

Madison Trujillo, Anupreet Kharbanda, Christa Corley, Pilar Simmons, Antiño R Allen

Antioxidants (Basel) . 2021 Aug 29;10(9):1383. doi: 10.3390/antiox10091383.

Abstract

In the past few years, breast cancer has become the most prevalent type of cancer. The majority of patients receive combinatorial chemotherapy treatments, which may result in increased risk of developing drug resistance, a reduced quality of life, and substantial side effects. Treatment modalities that could lessen the physical toll of standard treatments or act in synergy with chemotherapeutic treatments would benefit women worldwide. Research into tocotrienols has thus far demonstrated their potential to be such an agent, with tocotrienols surpassing the pharmacological potential of tocopherols. Further research using in vitro and preclinical breast cancer models to support clinical trials is needed. This review uses bibliometric analysis to highlight this gap in research and summarizes the current and future landscape of tocotrienols as an anti-breast cancer agent.

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Reduced infiltration of T-regulatory cells in tumours from mice fed daily with gamma-tocotrienol supplementation

Shonia Subramaniam, Jeya Seela Anandha Rao, Premdass Ramdas, Mei Han Ng, Methil Kannan Kutty, Kanga Rani Selvaduray, Ammu Kutty Radhakrishnan

Clin Exp Immunol . 2021 Jul 31. doi: 10.1111/cei.13650. Online ahead of print.

Abstract

Gamma-tocotrienol (γT3) is an analogue of vitamin E with beneficial effects on the immune system, including immune-modulatory properties. This study reports the immune-modulatory effects of daily supplementation of γT3 on host T-helper (Th) and T-regulatory (Treg) populations in a syngeneic mouse model of breast cancer. Female BALB/c mice were fed with either γT3 or vehicle (soy oil) for 2-weeks via oral gavage before they were inoculated with syngeneic 4T1 mouse mammary cancer cells (4T1 cells). Supplementation continued until the mice were sacrificed. Mice (n=6) were sacrificed at specified time-points for various analysis (blood leucocyte, cytokine production, and immunohistochemistry). Tumour volume was measured once every seven days. Gene expression studies were carried out on tumour-specific T-lymphocytes isolated from splenic cultures. Supplementation with γT3 increased CD4+ (p<0.05), CD8+ (p<0.05) T-cells and natural killer cells (p<0.05) but suppressed Treg cells (p<0.05) in peripheral blood when compared to animals fed with the vehicle. Higher interferon-gamma (IFNγ) and lower transforming growth factor-beta (TGF-ꞵ) levels were noted in the γT3 fed mice. Immunohistochemistry findings revealed higher infiltration of CD4+ cells, increased expression of interleukin-12 receptor-beta-2 (IL-12ꞵ2R), interleukin-24 (IL-24) and reduced expression of cells that express the forkhead box P3 (FoxP3) in tumours from the γT3 fed animals. Gene expression studies showed the downregulation of seven prominent genes in splenic CD4+ T-cells isolated from γT3-fed mice. Supplementation with γT3 from palm oil-induced T-cell dependent cell-mediated immune responses and suppressed Treg cells in the tumour microenvironment in a syngeneic mouse model of BC.

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Role of Vitamin E in Selected Malignant Neoplasms in Women

Anna Markowska, Michał Antoszczak, Janina Markowska, Adam Huczyński

Nutr Cancer . 2021 Jul 19;1-8. doi: 10.1080/01635581.2021.1952626. Online ahead of print.

Abstract

Vitamin E, which is actually a mixture of eight isoforms (four tocopherols and four tocotrienols), is a powerful antioxidant that protects polyunsaturated fatty acids against oxidation and has the ability to break the chain lipid peroxidation, which is used in the treatment of heart disease, atherosclerosis, muscle disorders or infertility among men. Studies in-vitro show that one of the effects of tocopherol is the reduction of cancer stem cell activity which is connected to poor clinical course. In the scientific literature, reports on the participation of vitamin E not only in protection against the mutagenic effects of reactive oxygen species, but also in its anti-angiogenic activity and the ability to inhibit the invasion and metastasis of neoplastic cells are increasingly common. In this context, the role of vitamin E in preventing the neoplastic process and selected malignant neoplasms among women seems to be of particular interest. In this article, we present the results of research on the potential anticancer effects of vitamin E in the fight against breast, cervical, endometrial and ovarian cancer.

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Evaluating Anticancer and Immunomodulatory Effects of Spirulina (Arthrospira) platensis and Gamma-Tocotrienol Supplementation in a Syngeneic Mouse Model of Breast Cancer

Hemavathy Subramaiam, Wan-Loy Chu, Ammu Kutty Radhakrishnan, Srikumar Chakravarthi, Kanga Rani Selvaduray, Yih-Yih Kok

Nutrients . 2021 Jul 6;13(7):2320. doi: 10.3390/nu13072320.

Abstract

Nutrition can modulate host immune responses as well as promote anticancer effects. In this study, two nutritional supplements, namely gamma-tocotrienol (γT3) and Spirulina, were evaluated for their immune-enhancing and anticancer effects in a syngeneic mouse model of breast cancer (BC). Five-week-old female BALB/c mice were fed Spirulina, γT3, or a combination of Spirulina and γT3 (Spirulina + γT3) for 56 days. The mice were inoculated with 4T1 cells into their mammary fat pad on day 28 to induce BC. The animals were culled on day 56 for various analyses. A significant reduction (p < 0.05) in tumor volume was only observed on day 37 and 49 in animals fed with the combination of γT3 + Spirulina. There was a marked increase (p < 0.05) of CD4/CD127+ T-cells and decrease (p < 0.05) of T-regulatory cells in peripheral blood from mice fed with either γT3 or Spirulina. The breast tissue of the combined group showed abundant areas of necrosis, but did not prevent metastasis to the liver. Although there was a significant increase (p < 0.05) of MIG-6 and Cadherin 13 expression in tumors from γT3-fed animals, there were no significant (p > 0.05) differences in the expression of MIG-6, Cadherin 13, BIRC5, and Serpine1 upon combined feeding. This showed that combined γT3 + Spirulina treatment did not show any synergistic anticancer effects in this study model.

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γ-Tocotrienol reverses multidrug resistance of breast cancer cells through the regulation of the γ-Tocotrienol-NF-κB-P-gp axis

Yuedi Ding, Jun Fan, Zhenqiang Fan, Kai Zhang

J Steroid Biochem Mol Biol . 2021 May;209:105835. doi: 10.1016/j.jsbmb.2021.105835. Epub 2021 Feb 5.

Abstract

The problem of multidrug resistance (MDR) presents a major obstacle in the chemotherapy of cancer. The MDR phenotype is often linked to the overexpression of ATP-binding cassette (ABC) transporters, that pumps out and decreased intracellular drug accumulation. γ-Tocotrienol, an unsaturated tocopherol belonging to the vitamin E family, has been shown to reverse the MDR of MCF-7/Adr cell. To reveal the role of γ-tocotrienol-NF-κB-P-gp axis in the reversal process, the expression level of mdr1/P-gp was determined by real-time PCR and western blot, while NF-κB activity was detected by immunofluorescence and NF-κB transcriptional activity reporter assay. Besides, mdr1 promoter activity and P-gp transport capacity were measured with the effect of γ-tocotrienol and NF-κB agonist/antagonist. Results showed that γ-tocotrienol effectively inhibited the expression levels of mdr1 mRNA and P-gp protein. It is demonstrated that γ-tocotrienol also suppressed mdr1 promoter activity and the efflux activity of P-gp. In addition, the activation of NF-κB signaling pathway and the transcriptional activity of NF-κB were both reduced by γ-tocotrienol. Evidences also showed that the NF-κB pathway is really involved in the regulation of the expression and function of mdr1/P-gp. Taken together, we confirmed that γ-tocotrienol reversed the MDR of MCF-7/Adr through the signaling pathway of NF-κB and P-gp.

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Tuning mPEG-PLA/vitamin E-TPGS-based Mixed Micelles for Combined Celecoxib/Honokiol Therapy for Breast Cancer

Jiahui Sun, Jing Li, Qi Liu, Min Jiang, Mengjia Yang, Siwen Zhan, Tong Qiu, Kaiyong He, Xueqiong Zhang

Eur J Pharm Sci . 2020 Apr 15;146:105277. doi: 10.1016/j.ejps.2020.105277. Epub 2020 Feb 24.

Abstract

This study aimed to develop, evaluate, and optimize the mPEG-PLA/vitamin E-TPGS mixed micelle drug delivery system to encapsulate celecoxib (CXB) and honokiol (HNK) for intravenous treatment of breast cancer. To this end, we formulated CXB-loaded mPEG-PLA/vitamin E-TPGS (PV-CXB) and HNK-loaded mPEG-PLA/vitamin E-TPGS (PV-HNK) mixed micelles and analyzed their characteristics. The 4T1 cell line was used for cytotoxicity determination and cellular uptake experiments, and for establishing a 4T1-bearing mouse model for histopathology, immunofluorescence, terminal deoxynucleotidyl transferase-mediated nick end labeling, and Western blot analysis. The synergistic effects of PV-CXB and PV-HNK combination therapy were investigated in vitro and in vivo using the coefficient of drug interaction values. The mean size of PV-CXB and PV-HNK prepared with optimal formulation was approximately 50 nm, with a spherical shape. PV-CXB and PV-HNK combination therapy exhibited cytotoxicity in 4T1 cells in vitro. However, the toxicity of PV-CXB and PV-HNK combination therapy was not apparent in normal tissues (heart, liver, spleen, lung, and kidney) in vivo and reduced the expression of collagen fibers in tumor tissues. Moreover, the combination therapy reduced the expression of tumor growth biomarkers (Foxp3, CD4, Gr-1, CD11b, CD31, Ki67, FoxM1, and VEGF). In addition, the tumor cell apoptosis rate reached 45.71 ± 0.62%. The combined treatment with PV-CXB and PV-HNK showed synergistic effect both in vitro and in vivo. Thus, the PV-CXB and PV-HNK drug delivery system could be used as a potential combination therapy for breast cancer .

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Beta-Tocotrienol Exhibits More Cytotoxic Effects than Gamma-Tocotrienol on Breast Cancer Cells by Promoting Apoptosis via a P53-Independent PI3-Kinase Dependent Pathway

Idriss M, Hodroj MH, Fakhoury R, Rizk S

Biomolecules. 2020 Apr 9;10(4). pii: E577. doi: 10.3390/biom10040577.

Abstract

Studies on tocotrienols have progressively revealed the benefits of these vitamin E isoforms on human health. Beta-tocotrienol (beta-T3) is known to be less available in nature compared to other vitamin E members, which may explain the restricted number of studies on beta-T3. In the present study, we aim to investigate the anti-proliferative effects and the pro-apoptotic mechanisms of beta-T3 on two human breast adenocarcinoma cell lines MDA-MB-231 and MCF7. To assess cell viability, both cell lines were incubated for 24 and 48 h, with different concentrations of beta-T3 and gamma-T3, the latter being a widely studied vitamin E isoform with potent anti-cancerous properties. Cell cycle progression and apoptosis induction upon treatment with various concentrations of the beta-T3 isoform were assessed. The effect of beta-T3 on the expression level of several apoptosis-related proteins p53, cytochrome C, cleaved-PARP-1, Bax, Bcl-2, and caspase-3, in addition to key cell survival proteins p-PI3K and p-GSK-3 α/β was determined using western blot analysis. Beta-tocotrienol exhibited a significantly more potent anti-proliferative effect than gamma-tocotrienol on both cell lines regardless of their hormonal receptor status. Beta-T3 induced a mild G1 arrest on both cell lines, and triggered a mitochondrial stress-mediated apoptotic response in MDA-MB-231 cells. Mechanistically, beta-T3’s anti-neoplastic activity involved the downregulation of phosphorylated PI3K and GSK-3 cell survival proteins. These findings suggest that vitamin E beta-T3 should be considered as a promising anti-cancer agent, more effective than gamma-T3 for treating human breast cancer and deserves to be further studied to investigate its effects in vitro and on other cancer types.

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Enhanced Prevention of Breast Tumor Metastasis by Nanoparticle-Delivered Vitamin E in Combination with Interferon-Gamma

Wu Y, Liu J, Movahedi F, Gu W, Xu T, Xu ZP

Adv Healthc Mater. 2020 Feb 13:e1901706. doi: 10.1002/adhm.201901706. [Epub ahead of print]

Abstract

Preventing cancer metastasis is one of the remaining challenges in cancer therapy. As an efficient natural product, alpha-tocopheryl succinate (α-TOS), the most effective form of vitamin E, holds great anticancer potential. To improve its efficacy and bioavailability, lipid-coated calcium carbonate/phosphate (LCCP) nanoparticles (NPs) with folic acid and PEG modification are synthesized for efficient delivery of α-TOS to 4T1 cancer cells. The optimized LCCP-FA NPs (NP-TOS15) show an α-TOS loading efficiency of around 60%, and enhanced uptake by 4T1 metastatic cancer cells. Consequently, NP-TOS15 significantly enhance the anticancer effect in combination with interferon-gamma (IFN-γ) in terms of apoptosis facilitation and migration inhibition. Importantly, NP-TOS15 upregulate the anticancer immunity via downregulating program death ligand 1 (PD-L1) expression that is initially induced by IFN-γ, and remarkably prevent the lung metastasis, particularly in combination with IFN-γ. Further investigation reveals that this combination therapy also modulates the cytotoxic lymphocyte infiltration into the tumor microenvironment for tumor elimination. Taken together, the NP delivery of α-TOS in combination with IFN-γ provides an applicable strategy for cancer therapy.

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Advancing the Role of Gamma-Tocotrienol as Proteasomes Inhibitor: A Quantitative Proteomic Analysis of MDA-MB-231 Human Breast Cancer Cells

Ramdas P, Radhakrishnan AK, Abdu Sani AA, Kumari M, Anandha Rao JS, Abdul-Rahman PS

Biomolecules. 2019 Dec 21;10(1). pii: E19. doi: 10.3390/biom10010019.

Abstract

Tocotrienol, an analogue of vitamin E has been known for its numerous health benefits and anti-cancer effects. Of the four isoforms of tocotrienols, gamma-tocotrienol (γT3) has been frequently reported for their superior anti-tumorigenic activity in both in vitro and in vivo studies, when compared to its counterparts. In this study, the effect of γT3 treatment in the cytoplasmic and nuclear fraction of MDA-MB-231 human breast cancer cells were assessed using the label-free quantitative proteomics analysis. The cytoplasmic proteome results revealed the ability of γT3 to inhibit a group of proteasome proteins such as PSMA, PSMB, PSMD, and PSME. The inhibition of proteasome proteins is known to induce apoptosis in cancer cells. As such, the findings from this study suggest γT3 as a potential proteasome inhibitor that can overcome deficiencies in growth-inhibitory or pro-apoptotic molecules in breast cancer cells. The nuclear proteome results revealed the involvement of important nuclear protein complexes which hardwire the anti-tumorigenesis mechanism in breast cancer following γT3 treatment. In conclusion, this study uncovered the advancing roles of γT3 as potential proteasomes inhibitor that can be used for the treatment of breast cancer.

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γ-Tocotrienol Suppression of the Warburg Effect Is Mediated by AMPK Activation in Human Breast Cancer Cells

Dronamraju V, Ibrahim BA, Briski KP, Sylvester PW

Nutr Cancer. 2019;71(7):1214-1228. doi: 10.1080/01635581.2019.1599969.

Abstract

Cancer cell metabolism is characterized by aerobic glycolysis or the “Warburg effect”. Enhanced Akt signaling is associated with activation of various downstream enzymes involved in the glycolytic process, whereas activation of 5′-AMP-activated kinase (AMPK) acts to terminate energy expending mechanisms and decrease glycolytic enzyme expression. Studies were conducted to determine if the anticancer effects of γ-tocotrienol, are mediated through a suppression in aerobic glycolysis. Results show that treatment with 0-7 μM γ-tocotrienol throughout a 4-day culture period resulted in a dose-responsive increase in AMPK activation, and corresponding decrease in Akt activity in human MCF-7 and MDA-MB-231 breast cancer cells. γ-Tocotrienol treatment was also found to induce a dose-responsive decrease in phosphorylated-Fox03 (inactivated), a transcription factor that acts to inhibit in the levels of glycolytic enzyme, and this decrease was associated with a reduction in glycolytic enzyme levels and activity, as well as glucose consumption in these cells. PCR microarray analysis shows that γ-tocotrienol treatment decreases the expression of genes associate with metabolic signaling and glycolysis in MCF-7 and MDA-MB-231 breast cancer cells. In summary, these findings demonstrate that the anticancer effects of γ-tocotrienol are mediated, at least in part, by a suppression in the Warburg effect.

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