Intake of antioxidants and risk of type 2 diabetes in a cohort of male smokers

Kataja-Tuomola MK, Kontto JP, Männistö S, Albanes D, Virtamo J.

Eur J Clin Nutr. 2011 May;65(5):590-7. Epub 2011 Jan 19.

Background/Objectives: Oxidative stress may induce insulin resistance in peripheral tissues and impair insulin secretion from pancreatic β-cells. Antioxidants are suggested to decrease the risk of diabetes through reduction of oxidative stress. However, only a few studies exist on dietary antioxidants and the risk of type 2 diabetes. We investigated the association of dietary antioxidants with incident type 2 diabetes in the α-Tocopherol, β-Carotene Cancer Prevention Study cohort.

Subject/Method: The study cohort included 29,133 male smokers aged 50-69 years. During a median follow-up of 10.2 years 660 incident cases of diabetes were observed among the 25,505 men with a completed baseline food frequency questionnaire.

Results: Dietary α-tocopherol, β-tocopherol and β-tocotrienol were positively associated with the risk of diabetes when adjusted for age and supplementation (relative risk (RR) 1.17 (95% confidence interval (CI) 0.91-1.51) P for trend 0.02; RR 1.31 (95% CI 1.02-1.68) P for trend 0.01; RR 1.28 (95% CI 1.00-1.63) P for trend 0.01, respectively), but the association disappeared after multivariate adjustment (RR 0.92 (95% CI 0.71-1.19) P for trend 0.97; RR 1.06 (95% CI 0.82-1.36) P for trend 0.48; RR 1.04 (95% CI 0.80-1.35) P for trend 0.46, respectively). Other tocopherols and tocotrienols as well as vitamin C, carotenoids, flavonols and flavones had no association with risk of diabetes.

Conclusions: Dietary antioxidants were not associated with a decreased risk of incident diabetes in middle-aged male smokers.

The diterpene geranylgeraniol (all trans-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ol) suppresses the growth of human liver, lung, ovary, pancreas, colon, stomach and blood tumors with undefined mechanisms. We evaluated the growth-suppressive activity of geranylgeraniol in murine B16 melanoma cells. Geranylgeraniol induced dose-dependent suppression of B16 cell growth (IC(50) = 55 ± 13 µmol/L) following a 48-h incubation in 96-well plates. Cell cycle arrest at the G1 phase, manifested by a geranylgeraniol-induced increase in the G1/S ratio and decreased expression of cyclin D1 and cyclin-dependent kinase 4, apoptosis detected by Guava Nexin™ assay and fluorescence microscopy following acridine orange and ethidium bromide dual staining, and cell differentiation shown by increased alkaline phosphatase activity, contributed to the growth suppression. Murine 3T3-L1 fibroblasts were 10-fold more resistant than B16 cells to geranylgeraniol-mediated growth suppression. Geranylgeraniol at near IC(50) concentration (60 µmol/L) suppressed the mRNA level of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by 50%. The impact of geranylgeraniol on B16 cell growth, cell cycle arrest and apoptosis were attenuated by supplemental mevalonate, the product of HMG-CoA reductase that is essential for cell growth. Geranylgeraniol and d-δ-tocotrienol, a down-regulator of HMG-CoA reductase, additively suppressed the growth of B16 cells. These results support our hypothesis that mevalonate depletion mediates the tumor-specific growth-suppressive impact of geranylgeraniol. Geranylgeraniol may have potential in cancer chemoprevention and/or therapy.

γ-Tocotrienol (γ-T3) is a member of the vitamin E family. Recently, γ-T3 has attracted the attention of the scientific community due to its potent anticancer activity and other therapeutic benefits. The objective of this study was to develop and validate a simple and practical reversed-phase HPLC method with satisfactory sensitivity for the routine quantification of γ-T3 in rat and human plasma. The separation of γ-T3 from the plasma components was achieved with a C(18) reversed-phase column with an isocratic elution using a mixture of methanol, ethanol and acetonitrile (85:7.5:7.5, v/v/v) with a UV detection at 295 nm. γ-T3 was extracted from rat and human plasma by liquid-liquid extraction with an average recovery of 60%. The method proved linear in the range 100-5000 ng/mL. The inter-day precision ranged from 5.8 to 12.8% and the accuracy ranged from 92.4 to 108.5%, while the intra-day precision ranged from 0.7 to 7.9% in both rat and human plasma. This data confirm that the developed method has a satisfactory sensitivity, accuracy and precision for the quantification of γ-T3 in plasma. To assess its applicability the method was successfully applied to the quantitative analysis for pharmacokinetic studies of γ-T3 in rats administered a 10 mg/kg single oral dose.

γ-Tocotrienol is a novel inhibitor of constitutive and inducible STAT3 signalling pathway in human hepatocellular carcinoma: potential role as an antiproliferative, pro-apoptotic and chemosensitizing agent

Rajendran P, Li F, Manu KA, Shanmugam MK, Loo SY, Kumar AP, Sethi G.

Br J Pharmacol. 2011 May;163(2):283-98.

Background & Purpose: Activation of signal transducer and activator of transcription 3 (STAT3) play a critical role in the survival, proliferation, angiogenesis and chemoresistance of tumour cells. Thus, agents that suppress STAT3 phosphorylation have potential as cancer therapies. In the present study, we investigated whether the apoptotic, antiproliferative and chemosensitizing effects of γ-tocotrienol are associated with its ability to suppress STAT3 activation in hepatocellular carcinoma (HCC).

Experimental Approach: The effect of γ-tocotrienol on STAT3 activation, associated protein kinases and phosphatase, STAT3-regulated gene products, cellular proliferation and apoptosis in HCC cells was investigated.

Key Results: γ-Tocotrienol inhibited both the constitutive and inducible activation of STAT3 with minimum effect on STAT5. γ-Tocotrienol also inhibited the activation of Src, JAK1 and JAK2 implicated in STAT3 activation. Pervanadate reversed the γ-tocotrienol-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that γ-tocotrienol induced the expression of the tyrosine phosphatase SHP-1 and deletion of the SHP-1 gene by small interfering RNA abolished the ability of γ-tocotrienol to inhibit STAT3 activation. γ-Tocotrienol also down-regulated the expression of STAT3-regulated gene products, including cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1 and vascular endothelial growth factor. Finally, γ-tocotrienol inhibited proliferation, induced apoptosis and significantly potentiated the apoptotic effects of chemotherapeutic drugs (paclitaxel and doxorubicin) used for the treatment of HCC.

Conclusions & Implications: Overall, these results suggest that γ-tocotrienol is a novel blocker of the STAT3 activation pathway, with a potential role in future therapies for HCC and other cancers.

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γ-Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer

Campbell SE, Rudder B, Phillips RB, Whaley SG, Stimmel JB, Leesnitzer LM, Lightner J, Dessus-Babus S, Duffourc M, Stone WL, Menter DG, Newman RA, Yang P, Aggarwal BB, Krishnan K.

Free Radic Biol Med. 2011 May 15;50(10):1344-54. Epub 2011 Feb 16.

Regions along the Mediterranean and in southern Asia have lower prostate cancer incidence compared to the rest of the world. It has been hypothesized that one of the potential contributing factors for this low incidence includes a higher intake of tocotrienols. Here we examine the potential of γ-tocotrienol (GT3) to reduce prostate cancer proliferation and focus on elucidating pathways by which GT3 could exert a growth-inhibitory effect on prostate cancer cells. We find that the γ and δ isoforms of tocotrienol are more effective at inhibiting the growth of prostate cancer cell lines (PC-3 and LNCaP) compared with the γ and δ forms of tocopherol. Knockout of PPAR-γ and GT3 treatment show inhibition of prostate cancer cell growth, through a partially PPAR-γ-dependent mechanism. GT3 treatment increases the levels of the 15-lipoxygenase-2 enzyme, which is responsible for the conversion of arachidonic acid to the PPAR-γ-activating ligand 15-S-hydroxyeicosatrienoic acid. In addition, the latent precursor and the mature forms of TGFβ2 are down-regulated after treatment with GT3, with concomitant disruptions in TGFβ receptor I, SMAD-2, p38, and NF-κB signaling.

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