**7.7 Tocotrienols in liver cancer**

Previous studies have substantiated the anticarcinogenic effects of tocotrienols against hepatocellular carcinoma (HCC) through its effect on a number of important signalling pathways [42, 107, 109–111]. The potency of tocotrienol isoforms against HCC cells were regarded as delta-tocotrienol > beta-tocotrienol > alphatocotrienol > gamma-tocotrienol [111, 120]. Gamma-tocotrienol was thought to suppress the proliferation of HCC cells by overexpression of peroxiredoxin-4 (Prx4) [105]. Moreover, in HCC, gamma-tocotrienol intervention resulted in increased expression of Bax, caspase-8 and caspase-9; raising Bid fragmentation; suppressing STAT3 and its associated proteins such as Bcl-2, Bcl-xL, survivin, cyclin D1, Mcl-1, and VEGF. All these aforementioned mechanisms gave rise to the anti-proliferative and apoptotic effects in HCC. [107, 110].

Interestingly, palm oil tocotrienols (palmvitee) supplementation surprisingly diminished the progression of hepatocarcinogenesis initiated by chemical carcinogens such as diethylnitrosamine (DEN)/2-acetylaminofluorene (AAF) in rats [12, 112].

Specific tocotrienol isomers such as gamma and delta-tocotrienols also substantially decreased the progression of HCC in mouse xenograft and orthoptic models through the nullification of the Akt/mTOR signaling pathway [106, 109]. It was pertinent to note that both the gamma and delta-tocotrienols were sequestered only in tumour sites and not in normal tissues, which implied

that these tocotrienol isomers act specifically on the tumours [109]. In HCC, gamma-tocotrienols displayed lipid-lowering function, which might facilitate its anticarcinogenic activity [108, 135]. The mechanism in which tocotrienols exert its lipid-lowering ability includes the regulation of various lipogenic enzymes e.g., fatty acid synthase (FAS), sterol regulatory element-binding transcription factor 1(SREBF1), stearoyl CoA desaturase 1(SCD1) and carnitine palmitoyl transferase 1A (CPT-1A) [135].

In addition, the tocotrienols were also able to inhibit the upstream regulators of lipid homeostasis genes e.g., diacylglycerol O-acyltransferase 2 (DGAT2), apolipoprotein B (ApoB)-100, SREBP1/2 and HMGCR. These reactions will cause a reduction of TGs, cholesterol and very low-density lipoprotein (VLDL) secretion in HepG2 HCC cells [108]. Accordingly, these studies conjointly exposed the potential of tocotrienols in the prevention and treatment of HCC.
