tocotrienol--delta and Liver-Neoplasms

The complexity of hepatocellular carcinoma (HCC) signaling and the failure of pharmacological therapeutics reveal the significance of establishing new anti-cancer strategies. Interferon alpha (IFN-α) has been used as adjuvant therapy for reducing HCC recurrence and improving survival. Delta-tocotrienol (δ-tocotrienol), a natural unsaturated isoform of vitamin E, is a promising candidate for cancer treatment. In this study, we evaluated whether the combination of δ-tocotrienol with IFN-α displays significant advantages in the treatment of HCC cells. Results showed that the combination significantly decreased cell viability, migration and invasion of HCC cells compared with single therapies. Combining δ-tocotrienol and IFN-α enhanced the decrease in proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase (MMP) 7 and MMP-9. The combination also produced an enhancement of apoptosis together with increased Bax/Bcl-xL ratio and reactive oxygen species (ROS) generation. δ-tocotrienol induced Notch1 activation and changes in Erk and p38 MAPK signaling status. Blocking experiments confirmed that ROS and Erk are involved, at least in part, in the anti-cancer effects of the combined treatment. In conclusion, the combination of δ-tocotrienol with IFN-α therapy showed promising results for HCC cell treatment, which makes the combination of cytokine-based immunotherapy with natural products a potential strategy against liver cancer.

Topics: Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Humans; Interferon-alpha; Liver Neoplasms; Reactive Oxygen Species; Signal Transduction; Vitamin E

Tocotrienol (T3) has recently gained increasing interest due to its anti-cancer effect. Here, we investigated the modulating effect of δ and γ T3 on the Ras-Raf-MEK-ERK oncogenic upstream signaling pathway in human hepatocellular carcinoma HepG2 cells. The results indicated that T3 regulated the upstream signaling cascades of this pathway.

Topics: Carcinoma, Hepatocellular; Cell Proliferation; Chromans; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; MAP Kinase Kinase Kinases; raf Kinases; ras Proteins; Signal Transduction; Vitamin E

Present study aimed to elucidate the suppression of serum lipids by gamma- and delta-tocotrienol (γδT3).. The lipid-lowering effects of γδT3 were investigated using HepG2 liver cell line, hypercholesterolemic mice and borderline-high cholesterol patients.. In-vitro results demonstrated two modes of action. First, γδT3 suppressed the upstream regulators of lipid homeostasis genes (DGAT2, APOB100, SREBP1/2 and HMGCR) leading to the suppression of triglycerides, cholesterol and VLDL biosyntheses. Second, γδT3 enhanced LDL efflux through induction of LDL receptor (LDLr) expression. Treatment of LDLr-deficient mice with 1 mg/day (50 mg/kg/day) γδT3 for one-month showed 28%, 19% reduction in cholesterol and triglyceride levels respectively, whereas HDL level was unaltered. The lipid-lowering effects were not affected by alpha-tocopherol (αTP). In a placebo-controlled human trial using 120 mg/day γδT3, only serum triglycerides were lowered by 28% followed by concomitant reduction in the triglyceride-rich VLDL and chylomicrons. In contrast, total cholesterol, LDL and HDL remained unchanged in treated and placebo groups. The discrepancies between in-vitro, in-vivo and human studies may be attributed to the differential rates of post-absorptive γδT3 degradation and LDL metabolism.. Reduction in triglycerides synthesis and transport may be the primary benefit caused by ingesting γδT3 in human.

Topics: Animals; Apolipoprotein B-100; Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Cells, Cultured; Chromans; Diacylglycerol O-Acyltransferase; Female; Humans; Hydroxymethylglutaryl CoA Reductases; Lipoproteins, VLDL; Liver; Liver Neoplasms; Male; Mice; Mice, Knockout; Receptors, LDL; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Sterol Regulatory Element Binding Protein 2; Triglycerides; Vitamin E

We evaluated the antitumor activity of tocotrienol (T3) on human hepatoma Hep3B cells. At first, we examined the effect of T3 on the proliferation of human hepatoma Hep3B cells and found that gamma-T3 inhibited cell proliferation at lower concentrations and shorter treatment times than alpha-T3. Then, we examined the effect of gamma-T3 apoptosis induction and found that gamma-T3 induced poly (ADP-ribose) polymerase (PARP) cleavage and stimulated a rise in caspase-3 activity. In addition, gamma-T3 stimulated a rise in caspase-8 and caspase-9 activities. We also found that gamma-T3-induced apoptotic cell death was accompanied by up-regulation of Bax and a rise in the fragments of Bid and caspase-8. These data indicate that gamma-T3 induced apoptosis in Hep3B cells and that caspase-8 and caspase-9 were involved in apoptosis induction. Moreover, these results suggest that Bax and Bid regulated apoptosis induction by gamma-T3.

Topics: Apoptosis; Carcinoma, Hepatocellular; Caspase 3; Caspase 8; Caspase 9; Caspases; Cell Division; Cell Line, Tumor; Chromans; Gene Expression; Genes, bcl-2; Humans; Liver Neoplasms; Poly(ADP-ribose) Polymerases; Tocotrienols; Vitamin E