**7.2 Tocotrienols in colorectal cancer**

The potential advantages of tocotrienols in the treatment of colorectal cancer have been investigated for the past several years. It was recently established that the delta isomer of tocotrienol could potentially suppress the progression of colon cancer cells by downregulating Wnt-1, β-catenin, c-jun, and cyclin D1 signals [124]. Correspondingly, the gamma isomer of tocotrienol was able to hinder the expansion of HT-29 colon carcinoma cells through the suppression of Bcl-2 and increment of Bax and caspase-3 signals [82]. The delta isomer of tocotrienol was proclaimed to decrease telomerase activity by inhibiting PKC activity in colorectal adenocarcinoma cells, which subsequently causes the downregulation of c-Myc and human telomerase reverse transcriptase (hTERT) expression, thus indicating tocotrienols' anticarcinogenic potential [82, 84].

Furthermore, the gamma isomer of tocotrienol also significantly induced apoptosis *in vitro* and *in vivo* by downregulating NF-κB and its regulated gene products [80, 82]. Additionally, previous experiments have also claimed that tocotrienols suppressed colon carcinoma growth and initiated apoptosis by inactivating pAkt, upregulating CDK inhibitors (p21, p27), caspase-3, and − 9, and deregulating β-catenin/Tcf (T-cell factor) signalling [66, 81].

Remarkably, the tocotrienol-rich fraction (TRF) derived from palm oil also initiated apoptosis in colon carcinoma cells through the activation of p53 and alteration of Bax/Bcl2 ratio [85]. Furthermore, an in vivo study has established that TRF reduced the growth of human colon cancer mice xenografts via the inhibition of Wnt pathway [125]. In addition, past research has also demonstrated that the delta isomer of tocotrienol prevented the hypoxia-induced VEGF and IL-8 overexpression and decreased the HIF-1α expression, which subsequently inhibited the angiogenesis process in colon cancer cells [83, 126]. In summary, these studies strongly validated tocotrienols as promising neutraceuticals for the management of colon carcinoma.

#### **7.3 Tocotrienols in gastric cancer**

The gamma isomer of tocotrienol was first discovered to induce intrinsic apoptosis in human gastric cancer cells through the repression of the MAPK signalling [88, 89]. The gamma isomer of tocotrienol was also found to exhibit potent antimetastatic and anti-angiogenic activity in gastric carcinoma. Specifically, it inhibited cell migration and invasion potential, by lowering the expression of the matrix metalloproteinases MMP-2 and MMP-9 and by raising the levels of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) and TIMP-2 [86]. The gamma-tocotrienol also significantly prevented the over-expression of hypoxia-mediated HIF-1α and VEGF synthesis by alteration of the ERK signalling pathway [127]. Furthermore, gammatocotrienol significantly reduced the expression of VEGFR-2 in HUVEC cells grown in a conditioned medium of gastric adenocarcinoma cells [87]. Recently, a study had shown that the gamma-tocotrienol significantly inhibited human gastric cancer SGC-7901 and MGC-803 cellular growth in vitro as well as in xenograted mice through its effect on the NF-κB activity [128]. Additionally, gamma-tocotrienol was noted to intensify the anticarcinogenic activity of capecitabine in human gastric carcinoma cell lines, as well as in nude mice xenografted with human gastric carcinoma cells [129].
