Tomio Ichikawa

Induction of cytotoxicity in human lung adenocarcinoma cells by 6-O-carboxypropyl-α-tocotrienol, a redox-silent derivative of α-tocotrienol

Tocotrienols are one of the most potent anticancer agents of all natural compounds and the anticancer property may be related to the inactivation of Ras family molecules. The anticancer potential of tocotrienols, however, is weakened due to its short elimination half life in vivo. To overcome the disadvantage and reinforce the anticancer activity in tocotrienols, we synthesized a redox‐silent analogue of α‐tocotrienol (T3), 6‐O‐carboxypropyl‐α‐tocotrienol (T3E). We estimated the possibility of T3E as a new anticancer agent against lung adenocarcinoma showing poor prognosis based on the mutation of ras gene. T3E showed cytotoxicity against A549 cells, a human lung adenocarcinoma cell line with a ras gene mutation, in a dose‐dependent manner (0–40 μM), whereas T3 and a redox‐silent analogue of α‐tocopherol (T), 6‐O‐carboxypropyl‐α‐tocopherol (TE), showed much less cytotoxicity in cells within 40 μM. T3E cytotoxicity was based on the accumulation of cells in the G1‐phase of the cell‐cycle and the subsequent induction of apoptosis. Similar to this event, 24‐hr treatment of A549 cells with 40 μM T3E caused the inhibition of Ras farnesylation, and a marked decrease in the levels of cyclin D required for G1/S progression in the cell‐cycle and Bcl‐xL, a key anti‐apoptotic molecule. Moreover, the T3E‐dependent inhibition of RhoA geranyl‐geranylation is an inducing factor for the occurrence of apoptosis in A549 cells. Our results suggest that T3E suppresses Ras and RhoA prenylation, leading to negative growth control against A549 cells. In conclusion, a redox‐silent analogue of T3, T3E may be a new candidate as an anticancer agent against lung adenocarcinoma showing poor prognosis based on the mutation of ras genes.

Complexation of Tocotrienol with γ-Cyclodextrin Enhances Intestinal Absorption of Tocotrienol in Rats

To determine the bioavailability of tocotrienol complex with γ-cyclodextrin, the effects of tocotrienol/γ-cyclodextrin complex on tocotrienol concentration in rat plasma and tissues were studied. Rats were administered by oral gavage an emulsion containing tocotrienol, tocotrienol with γ-cyclodextrin, or tocotrienol/γ-cyclodextrin complex. At 3 h after administration, the plasma γ-tocotrienol concentration of the rats administered tocotrienol/γ-cyclodextrin complex was higher than that of the rats administered tocotrienol and γ-cyclodextrin. In order to determine the effect of complexation on tocotrienol absorption, rats were injected with Triton WR1339, which prevents the catabolism of triacylglycerol-rich lipoprotein by lipoprotein lipase, and then administered by oral gavage an emulsion containing tocotrienol, tocotrienol with γ-cyclodextrin, or tocotrienol/γ-cyclodextrin complex. The plasma γ-tocotrienol concentration of the Triton-treated rats administered tocotrienol/γ-cyclodextrin complex was higher than that of the other Triton-treated rats. These results suggest that complexation of tocotrienol with γ-cyclodextrin elevates plasma and tissue tocotrienol concentrations by enhancing intestinal absorption.