**7.5 Tocotrienols in pancreatic cancer**

The gamma-tocotrienol isomer halted pancreatic cancer progression, both in cellular and animal studies, through inhibition of NF-kB innate activation and consequently, inhibition of the gene products under NF surveillance e.g. as c-Myc, CXCR-4, cyclin D1, MMP-9 and VEGF, amongst others [96]. Besides, delta-tocotrienol exhibited its chemopreventive activity by inhibiting the growth of pancreatic intraepithelial neoplasm (PIN) in K-ras transgenic mouse model via suppression of the K-ras downstream gene products such as MEK/ERK, PI3K/Akt and NF-kB, and intensified Bax and caspase-3 activities [95].

Both cellular and animal work has ascertained that delta-tocotrienol initiated the G1 cell cycle arrest through increasing the nuclear accretion of p27 (Kip1). The tocotrienols also suppressed pancreatic carcinoma growth through the inhibition of ErbB2 and mevalonate signalling, as well as initiation of the caspase-dependent apoptotic pathway [79, 97, 131]. Delta-tocotrienol was found to trigger EGR-1 signalling, thus increased the expression of Bax and eventually turned-on the apoptotic process [94]. In a small-scale phase 1 clinical trial involving patients with pancreatic ductal neoplasia, gamma-tocotrienol administration was shown to be

safe and effective in increasing the cleaved caspase-3 level in the cells of the cancerous tissue, which indicated apoptosis of the cancer cells [132]. In addition, it was recently discovered that delta-tocotrienol significantly suppressed the pancreatic ductal adenocarcinoma (PDAC) and PDAC stem-like cells metastatic process in vivo [133].
