Effect of annatto-tocotrienols supplementation on the development of mammary tumors in HER-2/neu transgenic mice

Abstract

Tocotrienols (T3), the lesser known isomers of vitamin E, have been reported to possess anticancer activity both in in vitro and in vivo experimental models of rodents transplanted with parental tumors or treated with carcinogens. We investigated the effects of dietary supplementation with annatto-T3 (90% δ-T3 and 10% γ-T3) on the spontaneous development of mammary tumors in HER-2/neu transgenic mice. Underlying mechanisms of the antitumor effect were evaluated by studying apoptosis, senescent-like growth arrest, immune modulation, oxidative effect and the expression of HER-2/neu in tumoral mammary glands of transgenic mice and in vitro in human and mice tumor cell lines. Annatto-T3 supplementation delayed the development of mammary tumors, reducing the number and size of mammary tumor masses and those of lung metastases. In annatto-T3-supplemented mice, both apoptosis and senescent-like growth arrest of tumor cells were increased in mammary glands while no immune modulation was observed. In vitro, a dose-dependent inhibition of cell growth, increased apoptosis and senescent-like growth arrest and a time-dependent accumulation of reactive oxygen species were observed in tumor cells treated with annatto-T3 or purified δ-T3. Annatto-T3 reduced both HER-2/neu mRNA and p185(HER-2/neu) protein in tumors and in tumor cell lines. The results show that the antitumor effect of annatto-T3 supplementation in HER-2/neu transgenic mice is mainly related to the direct induction of oxidative stress, senescent-like growth arrest and apoptosis of tumor cells rather than to an immune modulation.

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

“…Furthermore, many of these micronutrients have anti-cancer properties [20], [116]. In a study in SK-BR-3 breast cancer cells and HER2/neu transgenic female mice, supplementation of vitamin E isomers tocotrienols reduced both HER2 mRNA and protein in cancer cell-line as well as in tumors [117]. It is worth noting that SK-BR-3 cells are HER2 positive but estrogen receptor negative (ER−) human breast adenocarcinoma cell-line; while HER2/neu or mouse mammary tumor virus (MMTV)-neu transgenic mouse model expresses activated form of the rat homolog of HER2 and develops spontaneous mammary adenocarcinomas.…”

Annatto Tocotrienol Induces a Cytotoxic Effect on Human Prostate Cancer PC3 Cells via the Simultaneous Inhibition of Src and Stat3

“…However, T3s, although found in low amounts in the human diet, are most abundant in rice, palm and annatto respectively. Rice contains about 50% T and 50% T3, whereas palm contains ~75% T3 and 25% T. Annatto ranks highest in T3 content (100%) and it is virtually tocopherol free (10). Since a-T attenuates T3-dependent anti-cancer activity (11), annatto T3 may be the most effective anti-cancer source of T3-rich oil.…”

EGR-1/Bax pathway plays a role in vitamin E δ-tocotrienol-induced apoptosis in pancreatic cancer cells

“…Vitamin E δ-tocotrienol, a natural vitamin E available in whole grains and cereals, has gathered much attention as a potential chemopreventive and/or chemotherapeutic agent [5, 23–25]. Numerous studies, utilizing in vitro and in vivo model systems, have illustrated δ-tocotrienol’s capacity to inhibit carcinogenesis and modulate a multitude of signaling pathways associated with cellular growth, apoptosis, angiogenesis, and metastases [3, 4, 6, 26, 27].…”