δ-Tocopherol inhibits the development of prostate adenocarcinoma in prostate specific Pten-/- mice.

Wang H, Yang X, Liu A, Wang G, Bosland MC, Yang CS

Carcinogenesis. 2017 Nov 7. doi: 10.1093/carcin/bgx128.

Abstract

The PTEN/PI3K/AKT axis plays a critical role in regulating cell growth, differentiation and survival. Activation of this signaling pathway is frequently found in human cancers. Our previous studies demonstrated that δ-tocopherol (δ-T) attenuates the activation of AKT by growth factor in prostate cancer cell lines, leading to inhibition of proliferation and induction of apoptosis. Herein, we investigated whether δ-T inhibits the development of prostate adenocarcinoma in prostate-specific Pten-/- (Ptenp-/-) mice in which the activation of AKT is the major driving force for tumorigenesis. By feeding Ptenp-/- mice with AIN93M or 0.2% δ-T supplemented diet starting at the age of 6 or 12 weeks, we found that δ-T treatment reduced prostate adenocarcinoma multiplicity at the age of 40 weeks by 53.3% and 42.7%, respectively. Immunohistochemical analysis demonstrated that the phosphorylation of AKT(T308) was reduced in the prostate of the mice administered the δ-T diet. Consistently, proliferation was reduced and apoptosis was increased in prostate lesions of mice on the δ-T diet. Oxidative stress, as determined by immunohistochemical staining of 8-OH-dG, was not altered during prostate tumorigenesis, nor was it affected by administration of δ-T. In contrast, α-tocopherol (δ-T) at 0.2% in the diet did not affect prostate adenocarcinoma multiplicity in the Ptenp-/- mice. This finding is consistent with data from our previous study that δ-T, but not δ-T, inhibits the activation of AKT and the growth of prostate cancer cells. Together, these results demonstrate that δ-T inhibits the development of prostate adenocarcinoma in Ptenp-/- mice, mainly through inhibition of AKT activation.

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Synergistic Impact of d-δ-Tocotrienol and Geranylgeraniol on the Growth and HMG CoA Reductase of Human DU145 Prostate Carcinoma Cells.

Yeganehjoo H, DeBose-Boyd R, McFarlin BK, Mo H

Nutr Cancer. 2017 May-Jun;69(4):682-691. doi: 10.1080/01635581.2017.1299876. Epub 2017 Mar 31.

Abstract

The growth-suppressive effect of d-δ-tocotrienol and geranylgeraniol is at least partially attributed to their impact on 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in the mevalonate pathway that provides essential intermediates for the posttranslational modification of growth-related proteins including RAS. We hypothesize that these agents synergistically impact cell growth based on their complementary mechanisms of action with HMG CoA reductase. d-δ-tocotrienol (0-40 µmol/L; half maximal inhibitory concentration [IC50] = 15 µmol/L) and geranylgeraniol (0-100 µmol/L; IC50 = 60 µmol/L) each induced concentration-dependent suppression of the growth of human DU145 prostate carcinoma cells. Blends of the two agents synergistically suppressed the growth of DU145 cells, with combination index values ranging 0.67-0.75. While 7.5 µmol/L d-δ-tocotrienol and 30 µmol/L geranylgeraniol individually had no impact on cell cycle distribution in DU145 cells, a blend of the agents induced cell cycle arrest at the G1 phase. The synergistic downregulation of the expression of HMG CoA reductase by 7.5 µmol/L d-δ-tocotrienol and 30 µmol/L geranylgeraniol was accompanied by a reduction in membrane K-RAS protein. Our finding supports the cancer chemopreventive action of plant-based diets and their isoprenoid constituents. Properly formulated isoprenoids and derivatives may provide novel approaches in prostate cancer prevention and therapy.

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Inhibitory effect of a redox-silent analogue of tocotrienol on hypoxia adaptation in prostate cancer cells.

Shiozawa N, Sugahara R, Namiki K, Sato C, Ando A, Sato A, Virgona N, Yano T.

Anticancer Drugs. 2017 Mar;28(3):289-297. doi: 10.1097/CAD.0000000000000460.

Abstract

Prostate cancer (PCa) is one of the most common cancers in Western countries and acquires a malignant phenotype, androgen-independent growth. PCa under hypoxia often has resistance to chemotherapy and radiotherapy. However, an effective therapy against PCa under hypoxia has not yet been established. In this report, we investigated the inhibitory effect of a redox-silent analogue of tocotrienol on the survival of a human androgen-independent PCa cell line (PC3) under hypoxia. We found that the redox-silent analogue exerted a cytotoxic effect on PC3 cells in a dose-dependent manner irrespective of either hypoxia or normoxia. Moreover, under hypoxia, the analogue dose dependently reduced the protein levels of hypoxia-inducible factor (HIF)-1α and HIF-2α. In addition, a specific inhibitor toward HIF-1α induced cytotoxicity on PC3 cells, whereas selective inhibition of HIF-2α exerted no effect. Furthermore, suppression of HIFs levels by the analogue in hypoxic PC3 cells was closely associated with the inactivation of Fyn, a member of the nonreceptor tyrosine kinase family, as confirmed by the action of a specific inhibitor toward the kinase (PP2). Taken together, these results suggest that the tocotrienol analogue could inhibit the survival of PC3 cells under hypoxia, mainly by the inhibition of Fyn/HIF-1α signaling, and this may lead to the establishment of a new effective therapy for androgen-independent PCa.

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A naturally occurring mixture of tocotrienols inhibits the growth of human prostate tumor, associated with epigenetic modifications of cyclin-dependent kinase inhibitors p21 and p27.

Huang Y, Wu R, Su ZY, Guo Y, Zheng X, Yang CS, Kong AN.

J Nutr Biochem. 2017 Feb;40:155-163. doi: 10.1016/j.jnutbio.2016.10.019. Epub 2016 Nov 4.

Abstract

Tocotrienols, members of the vitamin E family, have three unsaturated bonds in their side chains. Recently, it has been suggested that the biological effects of tocotrienols may differ from that of tocopherols. Several in vitro studies have shown that tocotrienols have stronger anticancer effects than tocopherols. VCaP cell line used in this study is from a vertebral bone metastasis from a patient with prostate cancer. Eight-week-old male NCr(-/-) nude mice were subcutaneously injected with VCaP-luc cells in matrigel and then administered a tocotrienol mixture for 8 weeks. The tocotrienol mixture inhibited the growth of human prostate tumor xenografts in a dose-dependent manner. The concentrations of tocotrienols and their metabolites were significantly increased in treatment groups. Tocotrienols inhibited prostate tumor growth by suppressing cell proliferation, which was associated with the induction of the cyclin-dependent kinase (CDK) inhibitors p21 and p27. In addition, tocotrienol treatment was associated with elevated H3K9 acetylation levels at proximal promoter regions of p21 and p27 and with decreased expression of histone deacetylases. Tocotrienols inhibited human prostate tumor growth, associated with up-regulation of the CDK inhibitors p21 and p27. Elevated expression of p21 and p27 could be partly due to the suppressed expression of HDACs.

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Inhibitory effect of a redox-silent analogue of tocotrienol on hypoxia adaptation in prostate cancer cells.

Shiozawa N, Sugahara R, Namiki K, Sato C, Ando A, Sato A, Virgona N, Yano T.

Anticancer Drugs. 2016 Dec 6. [Epub ahead of print]

Abstract

Prostate cancer (PCa) is one of the most common cancers in Western countries and acquires a malignant phenotype, androgen-independent growth. PCa under hypoxia often has resistance to chemotherapy and radiotherapy. However, an effective therapy against PCa under hypoxia has not yet been established. In this report, we investigated the inhibitory effect of a redox-silent analogue of tocotrienol on the survival of a human androgen-independent PCa cell line (PC3) under hypoxia. We found that the redox-silent analogue exerted a cytotoxic effect on PC3 cells in a dose-dependent manner irrespective of either hypoxia or normoxia. Moreover, under hypoxia, the analogue dose dependently reduced the protein levels of hypoxia-inducible factor (HIF)-1α and HIF-2α. In addition, a specific inhibitor toward HIF-1α induced cytotoxicity on PC3 cells, whereas selective inhibition of HIF-2α exerted no effect. Furthermore, suppression of HIFs levels by the analogue in hypoxic PC3 cells was closely associated with the inactivation of Fyn, a member of the nonreceptor tyrosine kinase family, as confirmed by the action of a specific inhibitor toward the kinase (PP2). Taken together, these results suggest that the tocotrienol analogue could inhibit the survival of PC3 cells under hypoxia, mainly by the inhibition of Fyn/HIF-1α signaling, and this may lead to the establishment of a new effective therapy for androgen-independent PCa.

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δ-Tocopherol inhibits receptor tyrosine kinase-induced AKT activation in prostate cancer cells.

Wang H, Hong J, Yang CS.

Mol Carcinog. 2016 Nov;55(11):1728-1738. doi: 10.1002/mc.22422.

Abstract

The cancer preventive activity of vitamin E is suggested by epidemiological studies and supported by animal studies with vitamin Eforms, γ-tocopherol and δ-tocopherol (δ-T). Several recent large-scale cancer prevention trials with high dose of α-tocopherol, however, yielded disappointing results. Whether vitamin E prevents or promotes cancer is a serious concern. A better understanding of the molecular mechanisms of action of the different forms of tocopherols would enhance our understanding of this topic. In this study, we demonstrated that δ-T was the most effective tocopherol form in inhibiting prostate cancer cell growth, by inducing cell cycle arrest and apoptosis. By profiling the effects of δ-T on the cell signaling using the phospho-kinase array, we found that the most inhibited target was the phosphorylation of AKT on T308. Further study on the activation of AKT by EGFR and IGFR revealed that δ-T attenuated the EGF/IGF-induced activation of AKT (via the phosphorylation of AKT on T308 induced by the activation of PIK3). Expression of dominant active PIK3 and AKT in prostate cancer cell line DU145 in which PIK3, AKT, and PTEN are wild type caused the cells to be reflectory to the inhibition of δ-T, supporting that δ-T inhibits the PIK3-mediated activation of AKT. Our data also suggest that δ-T interferes with the EGF-induced EGFR internalization, which leads to the inhibition of the receptor tyrosine kinase-dependent activation of AKT. In summary, our results revealed a novel mechanism of δ-T in inhibiting prostate cancer cell growth, supporting the cancer preventive activity δ-T.

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A naturally occurring mixture of tocotrienols inhibits the growth of human prostate tumor, associated with epigenetic modifications of cyclin-dependent kinase inhibitors p21 and p27.

Huang Y, Wu R, Su ZY, Guo Y, Zheng X, Yang CS, Kong AN.

J Nutr Biochem. 2016 Nov 4;40:155-163. doi: 10.1016/j.jnutbio.2016.10.019. [Epub ahead of print]

Abstract

Tocotrienols, members of the vitamin E family, have three unsaturated bonds in their side chains. Recently, it has been suggested that the biological effects of tocotrienols may differ from that of tocopherols. Several in vitro studies have shown that tocotrienols have stronger anticancer effects than tocopherols. VCaP cell line used in this study is from a vertebral bone metastasis from a patient with prostate cancer. Eight-week-old male NCr(-/-) nude mice were subcutaneously injected with VCaP-luc cells in matrigel and then administered a tocotrienol mixture for 8 weeks. The tocotrienol mixture inhibited the growth of human prostate tumor xenografts in a dose-dependent manner. The concentrations of tocotrienols and their metabolites were significantly increased in treatment groups. Tocotrienols inhibited prostate tumor growth by suppressing cell proliferation, which was associated with the induction of the cyclin-dependent kinase (CDK) inhibitors p21 and p27. In addition, tocotrienol treatment was associated with elevated H3K9 acetylation levels at proximal promoter regions of p21 and p27 and with decreased expression of histone deacetylases. Tocotrienols inhibited human prostate tumor growth, associated with up-regulation of the CDK inhibitors p21 and p27. Elevated expression of p21 and p27 could be partly due to the suppressed expression of HDACs.

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Colorectal Adenomas in Participants of the SELECT Randomized Trial of Selenium and Vitamin E for Prostate Cancer Prevention.

Lance P, Alberts DS, Thompson PA, Fales L, Wang F, San Jose J, Jacobs ET, Goodman PJ, Darke AK, Yee M, Minasian L, Thompson IM, Roe DJ.

Cancer Prev Res (Phila). 2016 Oct 24. pii: canprevres.0104.2016. [Epub ahead of print]

Abstract

Selenium and vitamin E micronutrients have been advocated for the prevention of colorectal cancer. Colorectal adenoma occurrence was used as a surrogate for colorectal cancer in an ancillary study to the Selenium and Vitamin E Cancer Prevention Trial (SELECT) for prostate cancer prevention. The primary objective was to measure the effect of selenium (as selenomethionine) on colorectal adenomas occurrence, with the effect of vitamin E (as alpha tocopherol) supplementation on colorectal adenoma occurrence considered as a secondary objective. Participants who underwent lower endoscopy while in SELECT were identified from a subgroup of the 35,533 men randomized in the trial. Adenoma occurrence was ascertained from the endoscopy and pathology reports for these procedures. Relative risk (RR) estimates and 95% confidence intervals (CI) of adenoma occurrence were generated comparing those randomized to selenium versus placebo and to vitamin E versus placebo based on the full factorial design. Evaluable endoscopy information was obtained for 6,546 participants, of whom 2,286 had 1+ adenomas. Apart from 21 flexible sigmoidoscopies, all the procedures yielding adenomas were colonoscopies. Adenomas occurred in 34.2% and 35.7%, respectively, of participants whose intervention included or did not include selenium. Compared with placebo, the RR for adenoma occurrence in participants randomized to selenium was 0.96 (95% CI, 0.90-1.02; P = 0.194). Vitamin E did not affect adenoma occurrence compared to placebo (RR = 1.03, 95% CI, 0.96-1.10; P = 0.38). Neither selenium nor vitamin E supplementation can be recommended for colorectal adenoma prevention.

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Serum Metabolomic Response to Long-Term Supplementation with all-rac-α-Tocopheryl Acetate in a Randomized Controlled Trial.

Mondul AM, Moore SC, Weinstein SJ, Evans AM, Karoly ED, Männistö S, Sampson JN, Albanes D.

J Nutr Metab. 2016;2016:6158436. Published online 2016 Oct 20. doi: 10.1155/2016/6158436

Abstract

Background. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a randomized controlled cancer prevention trial, showed a 32% reduction in prostate cancer incidence in response to vitamin E supplementation. Two other trials were not confirmatory, however. Objective. We compared the change in serum metabolome of the ATBC Study participants randomized to receive vitamin E to those who were not by randomly selecting 50 men from each of the intervention groups (50 mg/day all-racα-tocopheryl acetate (ATA), 20 mg/day β-carotene, both, placebo). Methods. Metabolomic profiling was conducted on baseline and follow-up fasting serum (Metabolon, Inc.). Results. After correction for multiple comparisons, five metabolites were statistically significantly altered (β is the change in metabolite level expressed as number of standard deviations on the log scale): α-CEHC sulfate (β = 1.51, p = 1.45 × 10-38), α-CEHC glucuronide (β = 1.41, p = 1.02 × 10-31), αtocopherol (β = 0.97, p = 2.22 × 10-13), γtocopherol(β = -0.90, p = 1.76 × 10-11), and βtocopherol (β = -0.73, p = 9.40 × 10-8). Glutarylcarnitine, beta-alanine, ornithine, and N6-acetyllysine were also decreased by ATA supplementation (β range 0.40 to -0.36), but not statistically significantly. Conclusions. Comparison of the observed metabolite alterations resulting from ATA supplementation to those in other vitamin E trials of different populations, dosages, or formulations may shed light on the apparently discordant vitamin E-prostate cancer risk findings.

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Dietary tocopherols inhibit PhIP-induced prostate carcinogenesis in CYP1A-humanized mice.

Chen JX, Li G, Wang H, Liu A, Lee MJ, Reuhl K, Suh N, Bosland MC, Yang CS.

Cancer Lett. 2016 Feb 1;371(1):71-8. doi: 10.1016/j.canlet.2015.11.010.

Abstract

Tocopherols, the major forms of vitamin E, exist as alpha-tocopherol (α-T), β-T, γ-T and δ-T. The cancer preventive activity of vitamin Eis suggested by epidemiological studies, but recent large-scale cancer prevention trials with high dose of α-T yielded disappointing results. Our hypothesis that other forms of tocopherols have higher cancer preventive activities than α-T was tested, herein, in a novel prostate carcinogenesis model induced by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a dietary carcinogen, in the CYP1A-humanized (hCYP1A) mice. Treatment of hCYP1A mice with PhIP (200 mg/kg b.w., i.g.) induced high percentages of mouse prostatic intraepithelial neoplasia (mPIN), mainly in the dorsolateral glands. Supplementation with a γ-T-rich mixture of tocopherols (γ-TmT, 0.3% in diet) significantly inhibited the development of mPIN lesions and reduced PhIP-induced elevation of 8-oxo-deoxyguanosine, COX-2, nitrotyrosine, Ki-67 and p-AKT, and the loss of PTEN and Nrf2. Further studies with purified δ-T, γ-T or α-T (0.2% in diet) showed that δ-T was more effective than γ-T or α-T in preventing mPIN formations and p-AKT elevation. These results indicate that γ-TmT and δ-T could be effective preventive agents of prostate cancer.

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