TABLE 2.

Chemopreventive and potential therapeutic effects of tocopherols and tocotrienols in preclinical PCa models

Time	Vitamin E forms and doses	PCa models	Key observations
Chemopreventive effects on carcinogen-induced PCa in rodents
1991	1% αT along with catechol (0.8%), resorcinol (0.8%), hydroquinone (0.8%), selenium (2 ppm), γ-orysanol (2%) for 40 wk [45]	DMAB-induced prostate carcinogenesis in male F344 rats	No significant effects on atypical hyperplasias and carcinomas of the prostate
2010	dl-αT at 2000 and 4000 mg/kg diet (equivalent to 0.2% and 0.4% diet), or L-selenomethionine (1.5 or 3 mg/kg) [46]	Testosterone plus estradiol-treated NBL rats	No effects on development of prostate carcinomas, whereas αT ↑ the incidence of adenocarcinomas of the mammary glands
2010	dl-αT at 2000 and 4000 mg/kg diet, or αT (500 or 2000 mg/kg) plus L-selenomethionine (3 mg/kg) for 13 mo [47]	Intravenous injection of MNU plus androgen stimulation in Wistar-Unilever (W/U) rats	No significant effects on PCa incidence or development
2013	γT-enriched diet (20 mg/kg) for 16 wk [50]	MNU plus testosterone (subcutaneously)-induced epithelial dysplasia in the ventral prostate of Wistar rats	γT ↓ MNU-induced epithelial dysplasia by 38%, epithelial proliferation, COX-2, and MMP-9 in the ventral prostate
2016	γTmT (0.3%) or individual tocopherols, i.e., γT, δT, or αT at 0.2% in diet [51]	PhIP-induced prostate carcinogenesis in the CYP1A-humanized (hCYP1A) mice	γTmT and individual tocopherols ↓ PhIP-induced mouse PINs by 66%. δT (↓60% PINs) is stronger than γT or αT (↓∼20% PINs) for this effect
Chemopreventive effects on PIN development or PIN to adenocarcinoma in genetically engineered models
2009	γT at 50-mg/kg, 100-mg/kg, and 200-mg/kg diet for 7–10 wk; αT at 50-mg/kg diet [49]	The transgenic rat for adenocarcinoma of prostate (TRAP) driven by probasin/SV40 T antigen	γT, in contrast to αT, ↓ multiplicity of prostate adenocarcinoma without affecting PIN, and ↑ caspase 3 and caspase 7 in prostate tissue
2009, 2012	γTmT at 0.1% in diet for 24 wk [52,53]	Oncogenic SV40-driven transgenic andenocarcinoma of mouse prostate (TRAMP) mice	γTmT ↓ palpable tumor incidence by 75% and ↓ % high-degrade PINs, and ↑Nrf2 and its targeted genes by ↓CpG methylation
2010	γTE-rich tocotrienols (TEs) at 0.1%, 0.3%, and 1% containing αTE, βTE, γTE, δTE, and αT at 13, 1, 19, 5, and 13%, respectively, in AIN-76A diet [54]	TRAMP mice	TEs dose-dependently ↓ tumor incidence (50%–70%), weight (by 75%) and high-grade neoplastic lesions, whereas ↑ BAD, caspase 3, p21, and p27
2018	δT or αT at 0.2% in diet from the age of 6 or 12–40 wk [48]	Male prostate-specific PTEN-knockout (PtenP−/−) mice	δT (intervention starting at 6 or 12 wk of age), but not αT, ↓ % and multiplicity of prostate adenocarcinoma by 43%–53%, p-AKT and Ki67, and ↑caspase 3, without affecting HGPINs
2022	δTE at 0.05% diet from age of 6 wk to 20 to 40 wk [55]	Male prostate-specific PTEN-knockout (PtenP−/−) mice	δTE ↓ % prostate adenocarcinoma by 32.7%, proliferation (Ki67), angiogenesis (CD31 and VEGFd), and ↑apoptosis (caspase 3)
Effects on the growth of relatively advanced PCa
2004	540 ppm αT (originally from Rovimix E 50 from DSM), 200 ppm lycopene, or their combination for 4-wk pretreatment and 18-d posttumor implantation [56]	1 × 105 MatLyLu Dunning prostate cells were injected into the ventral prostate of male Copenhagen rats	αT or lycopene but not their combination ↑ % of necrotic area in a cross-sectional view of prostate tumor tissue; αT ↓ androgen signaling and lycopene ↓ 5-α-reductase, both ↓ prostatic spermine–binding protein
2006	dl-αT acetate at 5 or 50 mg/kg BW, or lycopene at 5 or 50 mg/kg BW, or lycopene+αT (5 mg/kg BW each) [57]	Orthotopic PC-346C prostate xenograft model in NMRI nu/nu mice	Lycopene+αT but not either agent alone suppressed orthotopic growth of PC-346C prostate tumors by 73% and increased median survival time by 40%
2006	γTE at 400 mg/kg BW was injected subcutaneously in the neck of nude mice, which were then irradiated at the rear part of the body including the location of tumor [58]	Human PCa bone metastasizing PC3 cells implanted in athymic mice	The size of the tumors was ↓ by ∼40% only in γTE-injected and γTE-irradiated mice, whereas there was ↑ lipid peroxidation in tumors and kidney (potential side effect at kidney)
2010	γT at 200 mg/kg or its combination with lycopene (250 mg/kg diet) [59]	Dunning R3327H adenocarcinoma cells implanted in male Copenhagen rats	Neither γT nor its combination with lycopene had significant impact on tumor growth
2010	γTE at 50 mg/kg via intraperitoneally 5 times a week alone or coadministered with docetaxel (7.5 mg/kg via intraperitoneally) [60]	PC-3 human androgen-independent PCa in xenograft model	γTE and γTE+docetaxel ↓ tumor growth by 52% and 61%, respectively. γTE was accumulated in tumors, ↑apoptosis, and ↓ proliferation
2011	γT or γTE at 125 mg/kg BW by oral gavage 3 times a week for 5 wk [61]	Human LNCaP PCa xenograft model in nu/nu mice	γTE was stronger than γT in ↓ the growth of LNCaP xenograft (by 50%) min nude mice
2011	γTE (100 mg/kg daily) orally for 3 wk, and PCa cells were subcutaneously injected for another 4 wk; γTE-pretreated PCa cells injected subcutaneously or orthotopically in nude mice [62]	PC3-Luc cells subcutaneously or orthotopically injected in nude mice	γTE-pretreated cells resulted in ↓tumor incidence; γTE given orally also ↓tumor incidence
2014	Methaneseleninic acid (MSA) (40.95 μg/kg BW), γT1 (20.83 mg/kg) or γT2 (41.66 mg/kg BW) in corn oil, alone or in combinations by gavage (5 d/wk) for 14 d [63]	Human PCa 22Rv1 cell-implanted tumor in Nu/J mice	MSA+γT1 or γT2 but not other treatments ↓ tumor weight (∼25%); MSA+γT1 or MSA ↓ PSA
2014	αT or δT at 0.3% diet for 48 d [64]	LNCaP xenograft model in nude mice	δT, but not αT, ↓ LNCaP tumor size and weight, and induced apoptosis in tumors
2016	mTEs containing αTE, βTE, δTE, γTE, and αT (at 8.3, 1.5, 4.6, 11.4, and 6 g out of 100 g, respectively) at 200 or 400 mg/kg BW, by gavage 3 times a week for 8 wk [65]	VCaP human hormone-refractory PCa xenograft model in NCr-immunodeficient mice	The mTEs dose-dependently ↓ tumor growth and caused ↑ CDK inhibitors p21 and p27 and ↑H3K9 acetylation at their promoters with decreased expression of histone deacetylase

γTmT is γT-rich tocopherol mixtures often containing 57%–60% γT, 21%–24% δT, 12%–13% αT, and 0.5%–1.5% βT.

Abbreviations: DMAB, 3,2'-dimethyl-4-aminobiphenyl; HGPIN, high-grade prostatic intraepithelial neoplasia; MNU, N-methyl-N-nitrosourea; Nrf2, nuclear factor erythroid 2–related factor 2; PCa, prostate cancer; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; PIN, prostate intraepithelial neoplasia; mTEs, mixed tocotrienols; TRAMP, transgenic adenocarcinoma of the mouse prostate; TRAP, transgenic rat for adenocarcinoma of prostate; TRF, tocotrienol-rich fraction; ↓, suppress or inhibit; ↑, increase or enhance; ↔, show no effect.