TABLE 2.

In vivo anticancer effects of tocotrienols and their potential use as adjuvants in chemotherapy¹

Animal model	Vitamin E forms and doses	Outcomes
Pancreatic cancer
LSL-Kras(G12D)/+Pdx-1-Cre (KPC) pancreatic cancer mouse model	δTE at 200 mg/kg, po, twice a day for 12 mo (152)	δTE ↑ median survival (11.1 mo vs. 9.7 mo in controls), ↓ PanIN progression, and ↓ incidence of invasive cancer
LSL-Kras(G12D)/+LSLTrp53(R172H)/+Pdx-1-Cre (KPC) transgenic mouse model of pancreatic cancer	δTE (200 mg/kg), po, twice a day, or δTE (oral) combined with gemcitabine (100 mg/kg, i.p twice a week) (153)	δTE or the combination ↑ survival rate (70% or 90%) compared with 30% with gemcitabine alone, ↓ epithelial-to-mesenchymal transition, and ↑ antiproliferation markers (p21, p27)
Human MIA PaCa2 pancreatic cancer cells orthotopically implanted in athymic Nu/Nu mice.	γTE at 400 mg/kg bw, po, daily or γTE with gemcitabine at 25 mg/kg via i.p. twice a week (78)	γTE ↓ tumor growth (by 40%) and ↓ NF-κB; the combination was stronger than either agent
Human pancreatic cancer AsPc-1 xenograft model in female NIH SCID nude mice	αTE, βTE, γTE and δTE at 200 mg/kg (in olive oil) gavaged twice daily for 4 wk; or δTE plus gemcitabine (100 mg/kg, i.p, twice a week) (79)	δTE > γTE > other tocotrienols in ↓ tumor development. δTE ↓ NF-κB and targeted genes in tumors; the combination ↓ (50%) pancreatic tumor more strongly than δTE (40%)
Human pancreatic cancer (PANC-1) implanted in nude mice	γTE (50 mg/kg, i.p.) or its combination with gemcitabine (50 mg/kg, i.v) (23)	γTE did not affect tumor growth but the combination ↓ tumor growth by ∼50%
An orthotopic xenograft model of human PDA stem-like cells	δTE at 200 mg/kg, po, twice a day with or without gemcitabine (100 mg/kg, i.p., twice a week) for 4 wk (107)	δTE ↓ the growth (volume by 45%) and metastasis of gemcitabine-resistant PDA human stem-like cells.
Prostate cancer
PC3 human AIPCa in xenograft model	γTE at 50 mg/kg, i.p., 5 times/wk alone or coadminstered with docetaxel (7.5 mg/kg, i.p.) (154)	γTE or its combination with docetaxel ↓ tumor growth by 52% and 61%, respectively; γTE accumulated in tumors, ↑ apoptosis, and ↓ proliferation
LNCaP human prostate cancer xenograft model in Nu/Nu mice	γT or γTE at 125 mg/kg bw by oral gavage 3 times/wk for 5 wk (88)	γTE was stronger than γT in ↓ the growth of LNCaP xenograft (by 50%) in nude mice
VCaP human hormone-refractory prostate cancer xenograft model in NCr immunodeficient mice	mTEs containing αTE, βTE, δTE, γTE, and αT at 8.3, 1.5, 4.6, 11.4, and 6 g out of 100 g) at 200 or 400 mg/kg bw, by gavage 3 times/wk for 8 wk (112)	The mTEs dose-dependently ↓ tumor growth and ↑ CDK inhibitors p21 and p27 and ↑ H3K9 acetylation at their promoters with ↓ expression of histone deacetylase
Human prostate cancer bone metastasizing PC3 cells implanted in athymic mice	γTE at 400 mg/kg bw was injected subcutaneously in the necks of nude mice, which were then irradiated at the rear part of the body including the location of tumor (155)	The size of the tumors was ↓ by ∼40% only in γTE- injected and irradiated mice, whereas there was ↑ lipid peroxidation in tumors and kidney (potential side effect in kidney)
TRAMP mice	γTE-rich mTEs containing 13%, 1%, 19%, 5%, and 13% αTE, βTE, γTE, δTE, and αT, respectively, at 0.1%, 0.3%, and 1% in an AIN-76A diet (156)	Tocotrienols dose-dependently ↓ tumor incidence (50–70%), weight (by 75%), and high-grade neoplastic lesions, and ↑ BAD, caspase-3, p21, and p27
Breast cancer
Spontaneous mammary tumors in FVB/N HER-2/neu transgenic mice	Annatto tocotrienols (δTE and γTE at 9:1) at 50 or 100 mg/kg bw in olive oil by gavage 3 times/wk (157)	Tocotrienols dose-dependently ↓ tumor size/mass by 75% and lung metastases; ↑ apoptosis and cell senescence in mammary glands
Human breast cancer MDA-MB-231 xenograft model in nude mice	γTE (50 mg/kg, i.p.) or its combination with docetaxel (2 mg/kg, i.p.) (23)	The combination was much stronger than either alone in ↓ tumor growth by ≤80% and 40–50%, respectively.
Female Balb/c mice inoculated with 4T1 cells in mammary pad to induce tumor	TRF from palm oil (1 mg/d, oral) alone with i.v. injection of DCs pulsed with tumor lysate (158)	Although DC injection ↓ tumor growth, TRF plus DC impulse with tumor lysate showed stronger antitumor effects
Melanoma and skin cancer
Aggressive melanoma B6(F10) implanted in C57BL female mice	Study 1: γTE at 116 and 924 μmol/kg diet given 10 d before and 28 d after tumor cell implantation; study 2: γTE at 2 mmol/kg diet given after melanomas were established (159); δTE at 62.5 mg/kg bw + lovastatin at 12.5 mg/kg bw in diet (160)	γTE delayed and ↓ melanoma growth; γTE at 2 mmol/kg prolonged the survival of mice by 30%; the combination of δTE and lovastatin ↓ tumor weight but not either alone
B6(F10) melanoma or A431 human epidermoid carcinoma cells implanted in female immunodeficient Balb/c mice	Transferrin-bearing, multilamellar vesicles entrapping tocotrienol for improving uptake by cancer cells that overexpress transferrin receptors; daily tail vein injection of 10 μg TRF (αTE, γTE, δTE, and αT at 17.6%, 23.1%, 15.1%, and 15.3%) (161)	The novel tocotrienol formulation, but not free agent, led to complete tumor eradication for 40% of B16-F10 melanoma tumors and 20% of A431 epidermoid carcinoma tumors
Mice xenografted with A375 melanoma cells	δTE at 100 mg/kg gavaged in olive oil, daily, 5 d/wk (162)	δTE ↓ (by 60.6%) the growth and progression of melanoma
Liver, colon, and gastric cancer
Murine hepatoma MH134 xenograft in C3H/HeN mice	γTE and δTE (0.1%) in diet (95)	γTE and δTE ↓ the growth of hepatoma by 45% and 55% and were accumulated in tumor but not in normal tissues
AOM-DSS-induced colon cancer in male C57BL/6 mice	Supplementation with TRF with 0.03% tocopherols (mainly αT) + 0.07% mTEs; δTE/γTE (8:1) at 0.075% in diet for 77 d (163)	Compared with a control diet, a δTE/γTE diet ↓ tumor multiplicity by 42%, whereas TRF nonsignificantly affected tumor number
Orthotopic HCC patient xenograft model in Balb/c nude female mice	γTE at 3.25 mg/mouse via daily gavage (164)	γTE ↓ tumor growth by 65% and suppressed angiogenesis
Colon adenocarcinoma (DLD-1) xenograft in nude mice	Rice bran tocotrienols at 10 mg/mouse containing αTE, γTE, and δTE at 0.36, 9.22, and 0.42 mg via daily gavage (165)	Tocotrienols ↓ tumor growth and ↑ p21, p27, and caspase 3/9; ↓ Akt phosphorylation; δTE was stronger against hypoxic tumor cells than nomoxic cells
SW620 colon cancer cell–implanted xenograft model in Balb/c nude mice	TRFs from palm oil (αT, αTE, βTE, γTE, and δTE at 0.4%, 9.8%, 4.1%, 45.6%, and 40%) at 5, 10, and 20 mg/kg by gavage (166)	TRFs ↓ tumor growth by ≤70–80% and ↓ β-catenin and Wnt-1 expression in tumors
HCT116 human colon cancer cell–implanted tumor in athymic nu/nu mice	γTE at 100 mg/kg, po, or γTE with capecitabine (60 mg/kg, twice a week); corn oil as vehicle (167)	The combination of γTE and capecitabine was stronger than either agent alone in inhibition of tumor growth
SNU-5 gastric cancer cells implanted xenograft model	γTE at 1 mg/kg or its combination with capecitabine at 60 mg/kg via i.p. injection (122)	γTE ↓ gastric tumor growth by 66% and the combination was more effective (by >90%) in this effect

¹AIPCa, androgen-independent prostate cancer; AOM, azoxymethan; BAD, Bcl-2-associated death promoter; bw, body weight; CDK, cyclin-dependent kinase; DC, dendritic cell; DSS, dextran sodium sulfate; HCC, human hepatocellular carcinoma; HER-2, human epidermal growth factor receptor 2; mTE, mixed tocotrienol; PanIN, pancreatic intraepithelial neoplasm; PDA, pancreatic ductal adenocarcinoma; po, orally; SCID, severe-combined immunodeficient; TRAMP, transgenic adenocarcinoma of the mouse prostate; TRF, tocotrienol-rich fraction; αT, α-tocopherol; αTE, α-tocotrienol; βTE, β-tocotrienol; δTE, δ-tocotrienol; γTE, γ-tocotrienol; ↓, suppressed or inhibited; ↑, increased or enhanced; ↔, showed no effect.