δ- and γ-tocopherols inhibit phIP/DSS-induced colon carcinogenesis by protection against early cellular and DNA damages - PubMed (original) (raw)

. 2017 Jan;56(1):172-183.

doi: 10.1002/mc.22481. Epub 2016 May 13.

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δ- and γ-tocopherols inhibit phIP/DSS-induced colon carcinogenesis by protection against early cellular and DNA damages

Jayson X Chen et al. Mol Carcinog. 2017 Jan.

Abstract

Tocopherols, the major forms of vitamin E, are a family of fat-soluble compounds that exist in alpha (α-T), beta (β-T), gamma (γ-T), and delta (δ-T) variants. A cancer preventive effect of vitamin E is suggested by epidemiological studies. However, past animal studies and human intervention trials with α-T, the most active vitamin E form, have yielded disappointing results. A possible explanation is that the cancer preventive activity of α-T is weak compared to other tocopherol forms. In the present study, we investigated the effects of δ-T, γ-T, and α-T (0.2% in diet) in a novel colon cancer model induced by the meat-derived dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and promoted by dextran sodium sulfate (DSS)-induced colitis in CYP1A-humanized (hCYP1A) mice. PhIP/DSS treatments induced multiple polypoid tumors, mainly tubular adenocarcinomas, in the middle to distal colon of the hCYP1A mice after 10 wk. Dietary supplementation with δ-T and γ-T significantly reduced colon tumor formation and suppressed markers of oxidative and nitrosative stress (i.e., 8-oxo-dG and nitrotyrosine) as well as pro-inflammatory mediators (i.e., NF-κB p65 and p-STAT3) in tumors and adjacent tissues. By administering δ-T at different time periods, we obtained results suggesting that the inhibitory effect of δ-T against colon carcinogenesis is mainly due to protection against early cellular and DNA damages caused by PhIP. α-T was found to be ineffective in inhibiting colon tumors and less effective in attenuating the molecular changes. Altogether, we demonstrated strong cancer preventive effects of δ-T and γ-T in a physiologically relevant model of human colon cancer. © 2016 Wiley Periodicals, Inc.

Keywords: DSS; PhIP; chemoprevention; colon carcinogenesis; tocopherols.

© 2016 Wiley Periodicals, Inc.

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Conflict of interest statement

Conflicts of Interest:

No potential conflicts of interest were disclosed.

Figures

Figure 1

Figure 1. Inhibitory effect of different tocopherols on PhIP/DSS-induced colon tumorigenesis in male hCYP1A mice

A, dietary supplementation with δ-T and γ-T significantly reduced tumor multiplicity in male mice (Means ± SD for groups from left to right: 0, 0, 7.3±2.3, 2.7±2.2, 5.8±2.9, 3.2±1.6, and 4.6±2.5, respectively). B, dietary tocopherol supplementation did not alter tumor volumes (Means ± SD for groups from left to right: N/A, N/A, 18.7±17.6, 17.0±14.7, 19.5±13.7, 17.9±16.6, and 20.2±18.4, respectively). C, δ-T supplementation before (and not after) PhIP/DSS treatment significantly reduced tumor multiplicity in male mice (Means ± SD for groups from left to right: 6.4±2.2, 3.6 ±1.7, and 5.4±2.3, respectively). D, δ-T supplementation before or after PhIP/DSS treatment did not alter tumor volumes (Means ± SD for groups from left to right: 18.9±14.0, 16.8±12.0, and 16.7±13.9, respectively). Statistical analysis was done using two-tailed Student’s _t_-test or ANOVA-Dunnett (*******P<0.001, ******P<0.01, *****P<0.05).

Figure 2

Figure 2. Dietary tocopherols suppress oxidative and nitrosative stress and pro-inflammatory mediators in the PhIP/DSS-induced colon tumors and adjacent tissues

A & C, representative micrographs showing that δ-T and γ-T supplementations were more effective than α-T in attenuating the levels of 8-oxo-dG and nitrotyrosine, respectively, in the colon tumors and adjacent tissues. B & D, quantitative analysis of 8-oxo-dG and nitrotyrosine immunostaining, respectively, in the colon tumors and adjacent tissues. E & G, representative micrographs showing that δ-T and γ-T supplementation, but not α-T, significantly attenuated the levels of NF-κB and p-STAT3, respectively, in the colon tumors and adjacent tissues. F & H, quantitative analysis of NF-κB and p-STAT3 immunostaining, respectively, in the colon tumors and adjacent tissues. Scale bar represents 50μm. Data presented as mean ± SD (n=5). Statistical analysis was done using two-tailed Student’s _t_-test or ANOVA-Dunnett (*******P<0.001, ******P<0.01, *****P<0.05).

Figure 3

Figure 3. Dietary δ-T and γ-T reduce 8-oxo-dG and nitrotyrosine in colon mucosa of PhIP-treated mice at the early time points

A and C, representative micrographs of 8-oxo-dG and nitrotyrosine immunostaining, respectively, showing weak nuclear-positive staining in vehicle-treated mice on control diet, strong staining in PhIP-treated mice on control diet, and lowered levels of staining by δ-T or γ-T in PhIP-treated mice at 1, 3 and 7 days after PhIP administration. B and D, quantitative analysis of the 8-oxo-dG and nitrotyrosine immunostaining, respectively, of vehicle-treated mice and PhIP-treated mice on control (Ctrl), δ-T-, γ-T- and α-T-supplemented diets. Scale bar represents 50μm. Data presented as mean ± SD (n=4–5). Statistical analysis was done using ANOVA-Tukey’s test.

Figure 4

Figure 4. Dietary δ-T and γ-T reduce γH2AX and enhance cleaved caspase-3 in colon mucosa of PhIP-treated mice at the early time points

A, representative micrographs of γH2AX immunostaining showing weak nuclear-positive staining in vehicle-treated mice on control diet, strong staining in PhIP-treated mice on control diet, and lowered levels of staining in PhIP-treated mice on δ-T or γ-T diet at 1, 3 and 7 days after PhIP administration. B, quantitative analysis of γH2AX immunostaining of vehicle-treated mice (V) and PhIP-treated mice on control (Ctrl), δ-T-, γ-T- and α-T-supplemented diets. C, representative micrographs of cleaved caspase-3 immunostaining showing negligible staining in vehicle-treated mice on control diet, mild staining in PhIP-treated mice on control diet, and increased levels of staining in PhIP-treated mice on 0.2% δ-T or γ-T-supplemented diet at day 1 PhIP administration. D, quantitative analysis of cleaved caspase-3 immunostaining, respectively, of vehicle-treated mice (V) and PhIP-treated mice on control (Ctrl), δ-T-, γ-T- and α-T-supplemented diets. Scale bar represents 50μm. Data presented as mean ± SD (n=4–5). Statistical analysis was done using ANOVA-Tukey’s test.

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