Design and QSAR study of analogs of gamma-tocotrienol with enhanced antiproliferative activity against human breast cancer cells

Nikolic K, Agababa D.

J Mol Graph Model. 2009 Apr;27(7):777-83. Epub 2008 Nov 27.

Quantitative structure-activity relationships (QSAR) study has been performed for two sets of the antitumor drugs against human breast cancer MCF-7 cell lines, alpha-tocopherol and cholesterol derivatives. Constitutional, geometrical, physico-chemical and electronic descriptors (using the density functional theory, B3LYP/6-31G (d,p) basis set) were computed and analyzed. The most relevant of these descriptors were grouped and multiple linear regressions have been carried out. Optimal QSAR models with three and four variables, R(2)>0.95 and cross-validation parameter q(pre)(2)>0.88, were selected. Based on the QSAR study, novel vitamin-E derivatives (compounds D-1 and D-2) were designed and their antiproliferative activities were evaluated using the proposed regression models. Calculated antiproliferative activities of the designed compounds, IC(50) (D-1): 3.09 microM and IC(50) (D-2): 3.54 microM, were significantly stronger than anticancer effect of the other analyzed compounds IC(50): 4-1461 microM.

Suppression of NF-kappa beta signaling pathway by tocotrienol can prevent diabetes associated cognitive deficits

Kuhad A, Bishnoi M, Tiwari V, Chopra K.

Pharmacol Biochem Behav. 2009 Apr;92(2):251-9. Epub 2008 Dec 24.


Objective: The etiology of diabetes associated cognitive decline is multifactorial and involves insulin receptor down regulation, neuronal apoptosis and glutamatergic neurotransmission. The study was designed to evaluate the impact of tocotrienol on cognitive function and neuroinflammatory cascade in streptozotocin-induced diabetes.

Research design and method: Streptozotocin-induced diabetic rats were treated with tocotrienol for 10 weeks. Morris water maze was used for behavioral assessment of memory. Cytoplasmic and nuclear fractions of cerebral cortex and hippocampus were prepared for the quantification of acetylcholinesterase activity, oxidative-nitrosative stress, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), NFkappabeta and caspase-3.

Results: After 10 weeks of streptozotocin injection, the rats produced significant increase in transfer latency which was coupled with enhanced acetylcholinesterase activity, increased oxidative-nitrosative stress, TNF-alpha, IL-1beta, caspase-3 activity and active p65 subunit of NFkappabeta in different regions of diabetic rat brain. Interestingly, co-administration of tocotrienol significantly and dose-dependently prevented behavioral, biochemical and molecular changes associated with diabetes. Moreover, diabetic rats treated with insulin-tocotrienol combination produced more pronounced effect on molecular parameters as compared to their per se groups.

Conclusions: Collectively, the data reveal that activation of NFkappabeta signaling pathway is associated with diabetes induced cognitive impairment and point towards the therapeutic potential of tocotrienol in diabetic encephalopathy.

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Owing to the increasing interest in the health effects of antioxidant micronutrients on chronic diseases, a robust and rapid HPLC method for simultaneous measurement of coenzyme Q(10) (ubiquinone and ubiquinol), vitamin A (all-trans-retinol), vitamin E (tocopherols and tocotrienols) and carotenoids (lutein, zeaxanthin, beta-cryptoxanthin, lycopene and beta-carotene) was developed. Sample preparation and analytical conditions that would affect solubility and stability of these antioxidants were investigated and optimized. The mobile phase used was made up of acetonitrile, methanol, ethanol and tert-butanol without corrosive additives such as ammonium perchlorate and perchloric acid. Our results show that using two C(18) columns coupled with photodiode array, fluorescence and electrochemical detection, a comprehensive spectrum of 16 lipid-soluble antioxidants in 30 microL of plasma could be separated and quantified within 30 min. The chromatographic run time was about 3-fold faster and the sample size was about 5-fold smaller than when assays were performed separately using existing methods. The present method will be useful for dietary habit studies and for antioxidant status investigations.

Chemoprevention of tocotrienols: The mechanism of antiproliferative effects

Wada S.

Forum Nutr. 2009;61:204-16. Epub 2009 Apr 7.

Tocotrienols have been reported as antitumor agents and widely commercialized as an antioxidant dietary supplement. Tocotrienols have more significant biological activity than tocopherols, although serum level of tocotrienols is much lower than that of tocopherols. This may be because intracellular concentration of tocotrienols was revealed to be significantly higher compared with tocopherols, and tocotrienol accumulation is observed in tumor. Previous reports have suggested antiproliferative effect, induction of apoptosis, modulation of cell cycle, antioxidant activity, inhibition of angiogenesis, and suppression of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity as anticarcinogenesis mechanisms of tocotrienols both in vivo and in vitro. Extension of the duration of host survival was observed in tumor-implanted mice treated with tocotrienol. Tocotrienols induce apoptosis mainly via mitochondria-mediated pathway. Cell cycle arrest is due to suppression of cyclin D bytocotrienols. Tocotrienols also inhibit vascularization-reducing proliferation, migration and tube formation. Malignant proliferation demands elevation of HMG CoA reductase activity, and tocotrienols suppress its activity. Tocotrienol treatment decreases oncogene expression and increases the level of tumor suppressors. Only a few clinical trials to determine the effects of tocotrienol on cancer prevention or treatment have been carried out. There is no convincing or probable evidence of the role of tocotrienols in cancer prevention, while alpha-tocopherol has been suggested to have a limited anti-prostate cancer potential. Neither beneficial activity nor adverse effect of tocotrienol has sufficiently been explored so far. The above-mentioned mechanisms of tocotrienols seem to be promising for cancer prevention; however, further clinical studies are warranted to assess the efficacy and safety of tocotrienol.

Towards the interaction mechanism of tocopherols and tocotrienols (Vitamin E) with selected metabolizing enzymes

Upadhyay J, Misra K. Source

Bioinformation. 2009 Apr 21;3(8):326-31.

Vitamin E is a mixture of eight compounds alpha, beta, gamma, delta- tocopherols and alpha, beta, gamma, delta- tocotrienols. Their individual role in cellular transport as antioxidants and in metabolic pathways has been highlighted in the present work. All the eight compounds have been docked with the respective metabolizing enzymes (alpha-tocopherol transfer protein (ATTP), alpha-tocopherol associated protein (TAP), P-glycoprotein (P-gly) and human serum albumin (HSA)) to understand molecular interactions for pharmacokinetics. These have been structurally aligned against the four human phospholipids in order to reveal their individual role in chylomicron formation and hence the mechanism of cellular transport. The study of their binding with their metabolizing enzymes provides insight to the comparative antioxidant activity of each of these isomers.

Delta-tocotrienol causes decrease of melanin content in mouse melanoma cells

Akihiro Michihara, Sachiyo Morita, Yae Hirokawa, Saya Ago, Kenji Akasaki and Hiroshi Tsuji

Journal of Health Science, 55(2) 314-318 (2009)

We examined the effect of –tocotrienol on melanin content in mouse melanoma B16 cells. Melanin content was significantly reduced in cells reated with 50 and 100µM δ–tocotrienol, but not 10µM δ–tocotrienol. The activity and amount of tyrosinase also significantly decreased in cells treated with 10, 50 and 100µM δ –tocotrienol. Furthermore, the mRNA level of tyrosinase as measured using real-time PCR was significantly decreased compared to controls in cells treated with 100µM δ–tocotrienol, but not 10 or 50µM δ–tocotrienol. These results indicated that at first δ-tocotrienol caused tyrosinase degradation, and then caused further decrease in the tyrosinase protein level via both tyrosinase degradation and a decrease in the mRNA level of tyrosinase. We conclude that the decrease of melanin content in the cells by δ–tocotrienol was the result of the decrease of the protein level of tyrosinase (tyrosinase degradation is more important than the decrease of mRNA).