TABLE 1.
Cancer-preventive effects of tocopherols in preclinical models1
| Animal model | Vitamin E forms and doses | Outcomes |
| Prostate cancer | ||
| NMU-induced epithelial dysplasia in the rat ventral prostate | γT-enriched diet (20 mg/kg) for 4 mo (124) | γT ↓ NMU-induced epithelial dysplasia by 38% and cell proliferation, COX-2, and MMP-9 in the ventral prostate |
| PhIP-induced prostate carcinogenesis in hCYP1A mice | γTmTs (0.3%) or tocopherols (i.e., γT, δT, or αT at 0.2% in diet) (125) | γTmTs or tocopherols ↓ PhIP-induced mouse PINs by 66%; δT was stronger than γT or αT in this effect |
| TRAP | γT at 50, 100, and 200 mg/kg diet for 7–10 wk; αT at 50 mg/kg diet (126) | γT, not αT, dose-dependently ↓ PIN to adenocarcinoma and ↑ apoptosis in prostate tissue |
| TRAMP mice | γTmTs at 0.1% in diet (113, 127) | γTmTs ↓ palpable tumor incidence by 75% and PINs and ↑ Nrf2 and its targeted genes by ↓ CpG methylation |
| LNCaP-xenograft model in nude mice | γT at 125 mg/kg bw 3 times/wk for 4 wk (88); αT or δT at 0.3% of diet for 48 d (128) | γT and δT, but not αT, ↓ the growth of LNCaP tumor by 30% and induced apoptosis in tumors |
| Dunning R3327H adenocarcinoma cells implanted in male Copenhagen rats | γT at 200 mg/kg or its combination with lycopene (250 mg/kg diet) (129) | Neither γT or its combination with lycopene had a significant impact on tumor growth |
| Human PCa cell 22Rv1-implanted tumor in Nu/J mice | MSA (40.95 μg/kg bw), γT at 20.83 or 41.66 mg/kg bw in corn oil, alone or in combinations by gavage (130) | Combination of MSA with γT showed the strongest ↓ tumor volume (∼25%), serum PSA and Ki67 |
| Colon cancer | ||
| AOM-induced ACF formation in the colon of male F344 rats | γTmTs at 0.1% of diet (131); δT, γT, αT, or γTmTs at 0.2% of diet (20); dl-α-tocopheryl acetate (500 mg/kg) (132) | γT, δT, or γTmTs (131) ↓ ACF with relative efficacy of δT (62%) > γT ∼γTmTs (48%) (20), whereas αT ↔ ACF (20, 132) |
| AOM-induced and DSS-promoted colon cancer in mice (polyps as endpoints) | γT at 0.1% of diet in male Balb/c mice (21); γTmTs at 0.17% and 0.3% in male CF-1 mice (133) | γT ↓ moderate colitis–promoted large-size tumors by 36–80% (21); γTmTs ↓ tumorigenesis, nitrotyrosine, PGE2, and LTB4 (133) |
| Colon tumorigenesis induced by PhIP/DSS in hCYP1A mice | γT, δT, or αT at 0.2% of diet starting 1 wk before PhIP administration and continuing until being killed; in some studies, δT intervention started after PhIP and DSS (134) | γT and δT (but not αT) ↓ tumor multiplicity by 45% and 64%, but not tumor volume, and ↓ oxidative stress, NF-κB, and STAT3; when intervention started after PhIP/DSS, δT was much less effective |
| Breast cancer | ||
| NMU-induced hormone-dependent mammary tumor in female Sprague-Dawley rats | γTmTs at 0.1%, 0.3%, and 0.5% (135, 136); αT, δT, or γT (0.3% diet) or γTmTs (0.3%) (137) | γTmTs ↓ tumor growth and multiplicity by 38%, 50%, and 80% and ↑ p21, p27, caspase 3, and PPAR-γ (136); δT and γT (not αT), ↓ tumor multiplicity or weight and ↑ apoptosis (137) |
| Estrogen 17β-estradiol E2-promoted mammary hyperplasia and tumor in ACI rats | γTmTs at 0.3% of diet for 1, 3, 7, and 14 d after estrogen implantation (138); γTmTs at 0.05%, 0.1%, 0.3%, and 0.5% of diet for 31 wk (139) | γTmTs ↔ E2-induced mammary hyperplasia, but ↓ oxidative stress (138); γTmTs (0.3% or 0.5%) ↓ tumor size by 52% or 42% and serum estradiol; ↑ CYP1A1 (metabolizing estrogen), ↑ Nrf2, and ↑ PPAR-γ (139) |
| ER+ MCF7 cancer cells orthotopically implanted in immunodeficient mice implanted with estrogen pellets | γTmTs at 0.05%, 0.1%, 0.3%, and 0.5% of diet for 9 wk (139) | γTmTs at all doses ↓ mammary tumor and appeared to be more effective in this model than ACI rats |
| MMTV/ErbB2/neu female transgenic mice that overexpress Her-2 | αT, γT, or δT (0.3% of diet) or γTmTs (0.3% of diet) for 35 wk (137) | Only γT diet ↑ the median tumor latency, but none of the treatment was effective in reducing tumor weight |
| Murine 66c1-4 GFP or MDA-MB231-GFP breast cancer cells implanted into mice | RRR-αT, synthetic αT, or RRR-γT at 358 or 2000 mg/kg diet (140, 141) | γT and synthetic αT, but not natural RRR-αT, ↓ mammary cancer growth and lung metastasis by 57%, whereas αT counteracted γT’s anticancer effect |
| Lung cancer | ||
| H1299 human lung cancer cell xenografts in NCr Nu/Nu mice | αT, γT, δT, and γTmTs at 0.17% or 0.3% of diet (142) | δT, γT, or γTmTs (not αT) ↓ tumor size by 50%, 35%, and 40%, respectively; ↓ DNA damage and nitrotyrosine; ↑ apoptosis |
| CL13 murine lung cancer cells implanted (subcutaneously) in A/J mice | γTmTs at 0.1% or 0.3% (143) | γTmTs ↓ the growth of CL13 tumors by 50–80% |
1
The typical formula of γTmTs contains 57–60% γT, 21–24% δT, 12–13% αT, and 0.5–1.5% βT. ACF, aberrant crypt foci; AOM, azoxymethan; bw, body weight; COX-2, cyclo-oxygenase 2; CYP1A1, cytochrome P4501A1; DSS, dextran sodium sulfate; ER+, estrogen receptor positive; hCYP1A, humanized CYP1A; LTB4, leukotriene B4; MMP-9, matrix metallopeptidase 9; MSA, methaneseleninic acid; NMU, N-methyl-N-nitrosourea; Nrf2, nuclear factor erythroid 2–related factor; PCa, prostate cancer; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; PIN, prostate intraepithelial neoplasia; PSA, prostate specific antigen; STAT3, signal transducer and activator of transcription factor 3; TRAMP, transgenic adenocarcinoma of the mouse prostate; TRAP, transgenic rat for adenocarcinoma of prostate; αT, α-tocopherol; βT, β-tocopherol; δT, δ-tocopherol; γT, γ-tocopherol; γTmT, γT-rich mixed tocopherol; ↓, suppressed or inhibited; ↑, increased or enhanced; ↔, showed no effect.