Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

Abstract

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 (γ and δ) 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.

Fig. 1

Schematic representation of the proposed relationship between uptake (cell content) and biological responsiveness to T3 treatment in vitro. T3 recruit different responses in cancer and non-cancer cells that range from cytoprotection to anti-cancer pro-apoptotic effects. The cell content of T3 appears to drive these responses through the modulation of different signaling pathways and groups of genes that link in a functional continuity the concentration-dependent and time-dependent responses to T3. Further details are reported in the text