Vitamin E derivatives bearing a carboxylic group have recently gained great attention because of their antitumoral properties. Garcinoic acid (trans-13'-carboxy-delta-tocotrienol) is a vitamin E analog extracted from Garcinia Kola seeds in which the carboxylic group is at the end of the aliphatic side chain and reported to be a racemate based on the optical rotation measurements. However, CD determination of a sample of the acid analyzed by us gave a positive peak at 208 nm, indicating that it is not a racemate. To assess the enantiomeric composition of garcinoic acid, it was thus transformed to alpha-tocopherol and analyzed by chiral HPLC on column OD-H. On the basis of the elution order of alpha-tocopherol stereoisomers, the garcinoic acid sample resulted to be enantiopure with R configuration at carbon 2 of the chroman ring. Moreover, in a preliminary test, the acid and some of its derivatives showed a marked antiproliferative effect on glioma C6 cancer cells.

The selective constraint of liver uptake and the sustained metabolism of tocotrienols (T3) demonstrate the need for a prompt detoxification of this class of lipophilic vitamers, and thus the potential for cytotoxic effects in hepatic and extra-hepatic tissues. Hypomethylated (c and d) forms of T3 show the highest in vitro and in vivo metabolism and are also the most potent natural xenobiotics of the entire vitamin E family of compounds. These stimulate a stress response with the induction of detoxification and antioxidant genes. Depending on the intensity of this response, these genes may confer cell protection or alternatively they stimulate a senescence-like phenotype with cell cycle inhibition or even mitochondrial toxicity and apoptosis. In cancer cells, the uptake rate and thus the cell content of these vitamers is again higher for the hypomethylated forms, and it is the critical factor that drives the dichotomy between protection and toxicity responses to different T3 forms and doses. These aspects suggest the potential for marked biological activity of hypomethylated ''highly metabolized'' T3 that may result in cytoprotection and cancer prevention or even chemotherapeutic effects. Cytotoxicity and metabolism of hypomethylated T3 have been extensively investigated in vitro using different cell model systems that will be discussed in this review paper as regard molecular mechanisms and possible relevance in cancer therapy.Keywords Tocotrienols Á Vitamin E Á Breast cancer Á Antioxidants Á Apoptosis Á Cell signaling Á Inflammation Á Metabolism Á Gene expression Á Cell redox T3 structure-function and specificity of actionIn the vitamin E family of molecules, tocotrienols (T3) are often considered of minor importance since these are less abundant than a and c tocopherol (TOH) in the circulation and in solid tissues. This has contributed to hinder our knowledge on the biological functions of this group of vitamers that is now regaining great interest, thanks to a number of recent studies that suggested health-promoting functions related with the cholesterol-lowering, cytoprotective, and anticarcinogenic effects of T3 [reviewed in (Aggarwal et al. (2010)].Structure-function studies demonstrate that many of these functions are more potent when the unsaturated (isoprenyl) side chain of T3 is combined with a hypomethylated (HM) chroman ring. The unsaturated chain characteristic of all the T3 forms confers well-defined physical and chemical characteristics that appear to include vitamer-specific interactions with other lipids and cell proteins (Atkinson

Contrary to concepts handed down in the literature from the early days of vitamin E research, one-electron oxidation of vitamin E does not involve 5a-C-centered radicals. A combined approach of analytical techniques, in particular electron paramagnetic resonance spectroscopy (EPR), organic synthesis of special derivatives, isotopic labeling, kinetic studies, and computational chemistry was used to re-evaluate the one-electron and two-electron oxidation chemistry of alpha-tocopherol (alpha-toc). EPR in combination with 5a-13C-labeled compounds provided no indication of the involvement of 5a-C-centered radicals. Oxidation of special tocopherol derivatives were used to disprove the occurrence of 5a-C-centered one-electron intermediates. Additionally it was shown that those vitamin E reactions that were commonly evoked to plead for the involvement of C-centered tocopheryl radicals actually proceeded via heterolytic, i.e., non-radical, intermediates. The results will help to clear widely spread misunderstandings about the chemistry of vitamin E and will have mechanistic implications for the synthesis of tocopherol-based supramolecular structures and 5a-substituted alpha-tocopherol derivatives.