Monthly Archives: June 2016

Exciting growth in palm phytonutrient segment

StarBiz  By Hanim Adnan

Local palm oil producers should focus on developing palm phytonutrient-based products, which have lately attracted good demand from the global neutraceuticals markets. The proven scientific health benefits of palm phytonutrients such as tocotrienols and carotenoids also bodes well with the growing health awareness and food safety concerns, which have led more consumers and manufacturers worldwide to source for natural, preservative-free and non-GMO ingredients in their products.

 

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Gamma-tocotrienol form of vitamin E suppresses breast cancer cell metastasis

Vitamin E is the collective name for a group of eight related vitamins, including four tocopherols (α, β, γ, and δ-tocopherol) and four tocotrienols (α, β, γ, and δ-tocotrienol). The eight variants have different distributions in foods and somewhat different biological activities. Alpha-tocopherol (α-tocopherol) is the most abundant form of vitamin E and is the isoform typically found in vitamin E supplements. Even brands containing mixed tocopherols do not contain any tocotrienols. However, evidence is accumulating that gamma-tocotrienol (γ-tocotrienol) is most effective in suppressing the proliferation of both hormone receptor positive (ER+/PR+) and triple negative (ER-/PR-/HER2-) breast cancer cells, as well as inducing their apoptosis (programmed cell death). Now a new study has reported that gamma-tocotrienol inhibits crucial steps in metastasis in a dose-response manner in both ER+/PR+ and triple negative cell

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Tocopherols in cancer: An update.

Das Gupta S, Suh N.

Mol Nutr Food Res. 2016 Jun;60(6):1354-63. doi: 10.1002/mnfr.201500847. Review.

Abstract

Tocopherols exist in four forms designated as α, β, δ, and γ. Due to their strong antioxidant properties, tocopherols have been suggested to reduce the risk of cancer. Cancer prevention studies with tocopherols have mostly utilized α-tocopherol. Large-scale clinical trials with α-tocopherol provided inconsistent results regarding the cancer-preventive activities of tocopherols. This review summarizes our current understanding of the anticancer activities of different forms of tocopherols based on follow-up of the clinical trials, recent epidemiological evidences, and experimental studies using in vitro and in vivo models. The experimental data provide strong evidence in support of the anticancer activities of δ-tocopherol, γ-tocopherol, and the natural tocopherol mixture rich in γ-tocopherol, γ-TmT, over α-tocopherol. Such outcomes emphasize the need for detailed investigation into the cancer-preventive activities of different forms of tocopherols to provide a strong rationale for intervention studies in the future.

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Metabolomic screening of pre-diagnostic serum samples identifies association between α- and γ-tocopherols and glioblastoma risk.

Björkblom B, Wibom C, Jonsson P, Mörén L, Andersson U, Johannesen TB, Langseth H, Antti H, Melin B.

Oncotarget. 2016 Jun 14;7(24):37043-37053. doi: 10.18632/oncotarget.9242.

Abstract

Glioblastoma is associated with poor prognosis with a median survival of one year. High doses of ionizing radiation is the only established exogenous risk factor. To explore new potential biological risk factors for glioblastoma, we investigated alterations in metabolite concentrations in pre-diagnosed serum samples from glioblastoma patients diagnosed up to 22 years after sample collection, and undiseased controls. The study points out a latent biomarker for future glioblastoma consisting of nine metabolites (γ-tocopherol, α-tocopherol, erythritol, erythronic acid, myo-inositol, cystine, 2-keto-L-gluconic acid, hypoxanthine and xanthine) involved in antioxidant metabolism. We detected significantly higher serum concentrations of α-tocopherol (p=0.0018) and γ-tocopherol(p=0.0009) in future glioblastoma cases. Compared to their matched controls, the cases showed a significant average fold increase of α- and γ-tocopherol levels: 1.2 for α-T (p=0.018) and 1.6 for γ-T (p=0.003). These tocopherol levels were associated with a glioblastoma odds ratio of 1.7 (α-T, 95% CI:1.0-3.0) and 2.1 (γ-T, 95% CI:1.2-3.8). Our exploratory metabolomics study detected elevated serum levels of a panel of molecules with antioxidant properties as well as oxidative stress generated compounds. Additional studies are necessary to confirm the association between the observed serum metabolite pattern and future glioblastoma development.

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Effect of maternal supplementation with vitamin E on the concentration of α-tocopherol in colostrum.

Melo LR, Clemente HA, Bezerra DF, Dantas RC, Ramalho HM, Dimenstein R.

J Pediatr (Rio J). 2016 Jun 18. pii: S0021-7557(16)30059-6. doi: 10.1016/j.jped.2016.03.007. [Epub ahead of print]

Abstract

This study aims to evaluate the effect of maternal supplementation with vitamin E on the concentration of α-tocopherol in colostrum and its supply to the newborn. Study results show that maternal vitamin E supplementation increases the supply of the vitamin to the infant by providing more than twice the Recommended Daily Intake.

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Enhanced effectiveness of tocotrienol-based nano-emulsified system for topical delivery against skin carcinomas.

Pham J, Nayel A, Hoang C, Elbayoumi T.

Drug Deliv. 2016 Jun;23(5):1514-24. doi: 10.3109/10717544.2014.966925.

Abstract

The potent anti-proliferative and pro-apoptotic actions of tocotrienols (T3) against cancer, but not normal tissues, have been hampered by their limited systemic bioavailabilty. Recent expansive development of diverse nanoemulsion (NE) vehicles emphasized their vast potential to improve the effective dosing of different clinical and experimental drugs of lipophilic nature, such as T3. The emphasis of the present work is to develop a pharmaceutically scalable, low-energy nano-emulsification approach for optimized incorporation of T3-rich palm oil (Tocomin®), possessing anticancer activity as a potential cutaneous delivery platform for adjunctive therapy of skin carcinomas, either alone or in combination with other chemotherapeutic agents. Different Tocomin®-NEs, obtained with different homogenization strategies, were screened based on physicochemical uniformity (droplet size, charge and polydispersity) and subjected to stress physical stability testing, along with chemical content analysis (≥90% Tocomin® – incorporation efficiency). Adopted hybrid nano-emulsification of Tocomin®, correlated with highest preservation of DPPH-radical scavenging capacity of active T3 in prototype formulation, Tocomin®-NE, which effectively permeated diffusion cell membranes 4-folds higher than propyleneglycol (PG)-admixed Tocomin® control. Against two different cell models of human cutaneous carcinoma, Tocomin®-hybrid NE demonstrated significantly stronger cytotoxic profiles (p ≤ 0.01), visible in both concentration- and time- dependent manners, with at least 5-folds lower IC50 values, compared to those estimated for the closest Tocomin®-control. The proposed hybrid nano-emulsified formulation of Tocomin® provides simple and stable delivery platform, for effective topical application against keratinocyte tumors.

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Vitamin E therapy beyond cancer: Tocopherol versus tocotrienol.

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

Pharmacol Ther. 2016 Jun;162:152-69. doi: 10.1016/j.pharmthera.2015.12.003. Review.

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 is 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 analogs and clinical pharmacology of vitamin E, it is likely that certain vitamin E isoform(s) will be therapeutic agents against human diseases besides cancer.

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Vitamin E metabolite 13′-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice.

Jang Y, Park NY, Rostgaard-Hansen AL, Huang J, Jiang Q.

Free Radic Biol Med. 2016 Jun;95:190-9. doi: 10.1016/j.freeradbiomed.2016.03.018.

Abstract

Vitamin E forms are substantially metabolized to various carboxychromanols including 13′-carboxychromanols (13′-COOHs) that are found at high levels in feces. However, there is limited knowledge about functions of these metabolites. Here we studied δT-13′-COOH and δTE-13′-COOH, which are metabolites of δ-tocopherol and δ-tocotrienol, respectively. δTE-13′-COOH is also a natural constituent of a traditional medicine Garcinia Kola. Both 13′-COOHs are much stronger than tocopherols in inhibition of pro-inflammatory and cancer promoting cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), and in induction of apoptosis and autophagy in colon cancer cells. The anticancer effects by 13′-COOHs appeared to be partially independent of inhibition of COX-2/5-LOX. Using liquid chromatography tandem mass spectrometry, we found that 13′-COOHs increased intracellular dihydrosphingosine and dihydroceramides after short-time incubation in HCT-116 cells, and enhanced ceramides while decreased sphingomyelins during prolonged treatment. Modulation of sphingolipids by 13′-COOHs was observed prior to or coinciding with biochemical manifestation of cell death. Pharmaceutically blocking the increase of these sphingolipids partially counteracted 13′-COOH-induced cell death. Further, 13′-COOH inhibited dihydroceramide desaturase without affecting the protein expression. In agreement with these mechanistic findings, δTE-13′-COOH significantly suppressed the growth and multiplicity of colon tumor in mice. Our study demonstrates that 13′-COOHs have anti-inflammatory and anticancer activities, may contribute to in vivo anticancer effect of vitamin E forms and are promising novel cancer prevention agents.

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Research: Healthy Effects of Black Pepper Fruits Extract, Tocotrienols, Terminalia Bellerica

Recent research supports the effects of natural ingredients, including black pepper fruits extract to increase mitochondrial function and Terminalia bellerica to reduce serum uric acid levels, while researchers further explore the heart and brain health effects of tocotrienols.

A recent human clinical study by the University of Georgia Department of Kinesiology found resveratrol fortified with black pepper fruits extract (as BioPerine® by Sabinsa) increased mitochondrial function. The study was conducted on participants who ingested a combo of resveratrol and BioPerine for four weeks with moderate exercise. Near infrared spectroscopy was used to study the mitochondrial capacity of wrist flexor muscle of one arm while the other arm served as the control. Results showed skeletal muscle mitochondrial performance increased with consumption of resveratrol (500 mg) and BioPerine (10 mg). The double-blind study was published in Applied Physiology, Nutrition and Metabolism.

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Synthesis of the vitamin E amino acid esters with an enhanced anticancer activity and in silico screening for new antineoplastic drugs.

Gagic Z, Ivkovic B, Srdic-Rajic T, Vucicevic J, Nikolic K, Agbaba D.

Eur J Pharm Sci. 2016 Jun 10;88:59-69. doi: 10.1016/j.ejps.2016.04.008.

Abstract

Tocopherols and tocotrienols belong to the family of vitamin E (VE) with the well-known antioxidant properties. For certain α-tocopherol and γ-tocotrienol derivatives used as the lead compounds in this study, antitumor activities against various cancer cell types have been reported. In the course of the last decade, structural analogs of VE (esters, ethers and amides) with an enhanced antiproliferative and proapoptotic activity against various cancer cells were synthesized. Within the framework of this study, seven amino acid esters of α-tocopherol (4a-d) and γ-tocotrienol (6a-c) were prepared using the EDC/DMAP reaction conditions and their ability to inhibit proliferation of the MCF-7 and MDA-MB-231 breast cancer cells and the A549 lung cancer cells was evaluated. Compound 6a showed an activity against all three cell lines (IC50: 20.6μM, 28.6μM and 19μM for the MCF-7, MDA-MB-231 and A549 cells, respectively), while compound 4a inhibited proliferation of the MCF-7 (IC50=8.6μM) and A549 cells (IC50=8.6μM). Ester 4d exerted strong antiproliferative activity against the estrogen-unresponsive, multi-drug resistant MDA-MB-231 breast cancer cell line, with IC50 value of 9.2μM. Compared with the strong activity of compounds 4a, 4d and 6a, commercial α-tocopheryl succinate and γ-tocotrienol showed only a limited activity against all three cell lines, with IC50 values >50μM. Investigation of the cell cycle phase distribution and the cell death induction confirmed an apoptosis of the MDA-MB-231 cells treated with 4d, as well as a synergistic effect of 4d with the known anticancer drug doxorubicin. This result suggests a possibility of a combined therapy of breast cancer in order to improve the therapeutic response and to lower the toxicity associated with a high dose of doxorubicin. The stability study of 4d in human plasma showed that ca. 83% initial concentration of this compound remains in plasma in the course of six hours incubation. The ligand based virtual screening of the ChEMBL database identified new compounds with a potential antiproliferative activity on MCF-7 and on multi-drug resistant MDA-MB 231 breast cancer cells.

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