Tocotrienols are members of the
vitamin E family but, unlike
tocopherols, possess an unsaturated
isoprenoid side chain that confers superior anti-
cancer properties. The ability of
tocotrienols to selectively inhibit the
HMG-CoA reductase pathway through posttranslational degradation and to suppress the activity of
transcription factor NF-κB could be the basis for some of these properties. Our studies indicate that γ- and δ-
tocotrienols have potent antiproliferative activity in
pancreatic cancer cells (Panc-28, MIA PaCa-2, Panc-1, and BxPC-3). Indeed both
tocotrienols induced cell death (>50%) by the MTT cell viability assay in all four
pancreatic cancer cell lines. We also examined the effects of the
tocotrienols on the AKT and the Ras/Raf/
MEK/ERK signaling pathways by Western blotting analysis. γ- and δ-
tocotrienol treatment of cells reduced the activation of
ERK MAP kinase and that of its downstream mediator RSK (
ribosomal protein S6 kinase) in addition to suppressing the activation of
protein kinase AKT. Suppression of activation of AKT by γ-
tocotrienol led to downregulation of p-GSK-3β and upregulation accompanied by nuclear translocation of Foxo3. These effects were mediated by the downregulation of Her2/ErbB2 at the messenger level.
Tocotrienols but not
tocopherols were able to induce the observed effects. Our results suggest that the
tocotrienol isoforms of
vitamin E can induce apoptosis in
pancreatic cancer cells through the suppression of vital cell survival and proliferative signaling pathways such as those mediated by the
PI3-kinase/AKT and
ERK/MAP kinases via downregulation of Her2/ErbB2 expression. The molecular components for this mechanism are not completely elucidated and need further investigation.