“First evidence that gamma-tocotrienol inhibits the growth of human gastric cancer and chemosensitizes it to capecitabine in a xenograft mouse model through the modulation of NF-kappaB pathway.”

Manu, K. A., Shanmugam, M. K., Ramachandran, L., Li, F., Fong, C. W., Kumar, A. P., Tan, P., Sethi, G.

Clin Cancer Res. 2012 Apr 15;18(8):2220-9.

Purpose: Because of poor prognosis and development of resistance against chemotherapeutic drugs, the existing treatment modalities for gastric cancer are ineffective. Hence, novel agents that are safe and effective are urgently needed. Whether gamma-tocotrienol can sensitize gastric cancer to capecitabine in vitro and in a xenograft mouse model was investigated.

Experimental Design: The effect of gamma-tocotrienol on proliferation of gastric cancer cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-kappaB activation by DNA-binding assay, and gene expression by Western blotting. The effect of gamma-tocotrienol on the growth and chemosensitization was also examined in subcutaneously implanted tumors in nude mice.

Results: gamma-Tocotrienol inhibited the proliferation of various gastric cancer cell lines, potentiated the apoptotic effects of capecitabine, inhibited the constitutive activation of NF-kappaB, and suppressed the NF-kappaB-regulated expression of COX-2, cyclin D1, Bcl-2, CXCR4, VEGF, and matrix metalloproteinase-9 (MMP-9). In a xenograft model of human gastric cancer in nude mice, we found that administration of gamma-tocotrienol alone (1 mg/kg body weight, intraperitoneally 3 times/wk) significantly suppressed the growth of the tumor and this effect was further enhanced by capecitabine. Both the markers of proliferation index Ki-67 and for microvessel density CD31 were downregulated in tumor tissue by the combination of capecitabine and gamma-tocotrienol. As compared with vehicle control, gamma-tocotrienol also suppressed the NF-kappaB activation and the expression of cyclin D1, COX-2, intercellular adhesion molecule-1 (ICAM-1), MMP-9, survivin, Bcl-xL, and XIAP.

Conclusions: Overall our results show that gamma-tocotrienol can potentiate the effects of capecitabine through suppression of NF-kappaB-regulated markers of proliferation, invasion, angiogenesis, and metastasis.

Comparative effect of TRF aTP and aTPA on inflammatory mediators and NF-KB expression in mouse peritoneal macrophages

Lean-Teik Ng, Huey-Jiun Ko

Food Chemistry 134 (2012) 920–925 Epub 16 March 2012

The effects of tocotrienol-rich fraction (TRF), a-tocopherol (T) and a-tocopheryl acetate (TA) on lipopolysaccharide (LPS)-induced inﬂammatory responses in mouse peritoneal macrophages were examined. Results showed that at 5–30 lg/ml, all test compounds plus 1 lg/ml LPS exhibited no cytotoxic effects on macrophage cells. Compared with T and TA, TRF showed the strongest anti-inﬂammatory activity as demonstrated by its potency in inhibiting the LPS-induced nitric oxide (NO), prostaglandin E2 (PGE2), and proinﬂammatory cytokine (TNF-a, IFN-c, IL-1b and IL-6) production. At 10 lg/ml, it signiﬁ-
cantly blocked the LPS induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, but has no effect on cyclooxygenase-1 (COX-1). Furthermore, TRF also showed a greater inhibition on the nuclear factor kappa B (NF-jB) expression than T and TA. These results suggest that TRF could be a better agent than T and TA for use in the prevention of chronic inﬂammatory diseases.

Novel drugs to ameliorate gastrointestinal normal tissue radiation toxicity in clinical practice: What is emerging from the laboratory?

Berbée M, Hauer-Jensen M.

Curr Opin Support Palliat Care. 2012 Mar;6(1):54-9.

Purpose of Review: To give an overview of promising novel agents under development for the prevention and reduction of gastrointestinal radiation injury.

Recent Findings: Currently, several novel agents are being tested as drugs to prevent or reduce gastrointestinal radiation injury. These drugs may not only prevent injury, but also mitigate toxicity, that is, reduce injury after radiation exposure has occurred. Promising novel agents include the somatostatin analogue SOM230, growth factors, agents acting on the toll-like receptor 5 pathway, endothelial protectants, and the vitamin E analogue γ-tocotrienol.

Summary: Gastrointestinal radiation injury is the most important dose-limiting factor during radiotherapy of the abdomen or pelvis. It may severely affect the quality of life both during radiotherapy treatment and in cancer survivors. To date, there are no agents that can prevent or reduce intestinal radiation injury. Hence, there is an urgent need for the development of novel drugs to ameliorate intestinal toxicity during and after radiotherapy. This review summarizes the several agents that have been shown to reduce intestinal radiation injury in animals. Further research is needed to investigate their safety and efficacy in patients receiving radiotherapy for abdominal or pelvic tumours.

Oral tocotrienols are transported to human tissues and delay the progression of the model for end-stage liver disease score in patients

Patel V, Rink C, Gordillo GM, Khanna S, Gnyawali U, Roy S, Shneker B, Ganesh K, Phillips G, More JL, Sarkar A, Kirkpatrick R, Elkhammas EA, Klatte E, Miller M, Firstenberg MS, Chiocca EA, Nesaretnam K, Sen CK.

J Nutr. 2012 Mar;142(3):513-9. Epub 2012 Feb 1.

Abstract

The natural vitamin E family is composed of 8 members equally divided into 2 classes: tocopherols (TCP) and tocotrienols (TE). A growing body of evidence suggests TE possess potent biological activity not shared by TCP. The primary objective of this work was to determine the concentrations of TE (200 mg mixed TE, b.i.d.) and TCP [200 mg α-TCP, b.i.d.)] in vital tissues and organs of adults receiving oral supplementation. Eighty participants were studied. Skin and blood vitamin E concentrations were determined from healthy participants following 12 wk of oral supplementation of TE or TCP. Vital organ vitamin E levels were determined by HPLC in adipose, brain, cardiac muscle, and liver of surgical patients following oral TE or TCP supplementation (mean duration, 20 wk; range, 1-96 wk). Oral supplementation of TE significantly increased the TE tissue concentrations in blood, skin, adipose, brain, cardiac muscle, and liver over time. α-TE was delivered to human brain at a concentration reported to be neuroprotective in experimental models of stroke. In prospective liver transplantation patients, oral TE lowered the model for end-stage liver disease (MELD) score in 50% of patients supplemented, whereas only 20% of TCP-supplemented patients demonstrated a reduction in MELD score. This work provides, to our knowledge, the first evidence demonstrating that orally supplemented TE are transported to vital organs of adult humans. The findings of this study, in the context of the current literature, lay the foundation for Phase II clinical trials testing the efficacy of TE against stroke and end-stage liver disease in humans.

Trial registration: ClinicalTrials.gov NCT00678834.

Analyses of tocols (tocopherols and tocotrienols) in palm oil have been extensively reported in the past. However, due to the scarcity of individualtocotrienol standards, calibrations have mostly been carried out using only α-tocopherol as standard. Moreover, even if the individual tocotrienols are being used, their reliability is often questioned, because tocotrienols are highly susceptible to oxidation and deterioration. This paper reports on the study of the deterioration rate of individual tocotrienol standards upon storage as well as different calibration methods for the tocols in palm oil.

The separation and determination of tocopherols (Ts) and tocotrienols (T3s) by reversed-phase high-performance liquid chromatography with fluorescence detection has been developed and validated after optimization of various chromatographic conditions and other experimental parameters. Analytes were separated on a PerfectSil Target ODS-3 (250 × 4.6 mm, 3 μm) column filled with a novel sorbent material of ultrapure silica gel. The separation of Ts and T3s was optimized in terms of mobile-phase composition and column temperature on the basis of the best compromise among efficiency, resolution, and analysis time. Using a gradient elution of mobile phase composed of isopropanol/water and 7 °C column temperature, a satisfactory resolution was achieved within 62 min. For the quantitative determination, α-T acetate (50 μg/mL) was used as the internal standard. Detection limits ranged from 0.27 μg/mL (γ-T) to 0.76 μg/mL (γ-T3). The validation of the method was examined performing intraday (n = 5) and interday (n = 3) assays and was found to be satisfactory, with high accuracy and precision results. Solid-phase extraction provided high relative extraction recoveries from cereal samples: 87.0% for γ-T3 and 115.5% for δ-T. The method was successfully applied to cereals, such as durum wheat, bread wheat, rice, barley, oat, rye, and corn.

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