Antiproliferative and Apoptotic Effects of Tocopherols and Tocotrienols on Preneoplastic and Neoplastic Mouse Mammary Epithelial Cells

Abstract

Studies were conducted to determine the comparative effects of tocopherols and tocotrienols on preneoplastic (CL-S1), neoplastic (-SA), and highly malignant (+SA) mouse mammary epithelial cell growth and viability in vitro. Over a 5-day culture period, treatment with 0-120 microM alpha- and gamma-tocopherol had no effect on cell proliferation, whereas growth was inhibited 50% (IC50) as compared with controls by treatment with the following: 13, 7, and 6 microM tocotrienol-rich-fraction of palm oil (TRF); 55, 47, and 23 microM delta-tocopherol; 12, 7, and 5 microM alpha-tocotrienol; 8, 5, and 4 microM gamma-tocotrienol; or 7, 4, and 3 microM delta-tocotrienol in CL-S1, -SA and +SA cells, respectively. Acute 24-hr exposure to 0-250 microM alpha- or gamma-tocopherol (CL-S1, -SA, and +SA) or 0-250 microM delta-tocopherol (CL-S1) had no effect on cell viability, whereas cell viability was reduced 50% (LD50) as compared with controls by treatment with 166 or 125 microM delta-tocopherol in -SA and +SA cells, respectively. Additional LD50 doses were determined as the following: 50, 43, and 38 microM TRF; 27, 28, and 23 microM alpha-tocotrienol; 19, 17, and 14 microM gamma-tocotrienol; or 16, 15, or 12 microM delta-tocotrienol in CL-S1, -SA, and +SA cells, respectively. Treatment-induced cell death resulted from activation of apoptosis, as indicated by DNA fragmentation. Results also showed that CL-S1, -SA, and +SA cells preferentially accumulate tocotrienols as compared with tocopherols, and this may partially explain why tocotrienols display greater biopotency than tocopherols. These data also showed that highly malignant +SA cells were the most sensitive, whereas the preneoplastic CL-S1 cells were the least sensitive to the antiproliferative and apoptotic effects of tocotrienols, and suggest that tocotrienols may have potential health benefits in preventing and/or reducing the risk of breast cancer in women.

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

“…The higher potency of T3 as compared to TOH forms as inhibitors of cell growth in preneoplastic and even more in neoplastic mouse mammary epithelial cells (McIntyre et al 2000), has been attributed to a preferential uptake of T3, which rapidly provides cell levels critical for the generation of a stress response and cytotoxic effects ). Recent data obtained in TUBO murine breast cancer cells, showed that the anti-cancer effect of d-T3 follows the same cell uptake-dependent mechanism [ , manuscript in preparation].…”

“…Indeed, the majority of data obtained assessing the antiproliferative and pro-apoptotic activity of HM T3 in different breast cancer cell lines showed IC50 values between 3 and 30 lM (Table 2) while in non-mammary cells IC50 values are between 20 and 70 lM ( Table 3). The lowest IC50 levels in breast cancer cells (McIntyre et al 2000) were obtained by means of days of in vitro exposure to concentrations of HM T3 that are close to, but lower than, the levels of c-and d-T3 found in human and animal plasma after supplementation (Lodge et al 2001;Mustad et al 2002). Furthermore, half life of all T3 investigated in humans (a, c, d) are 4.5-8.7 times shorter than those of a-TOH (Yap et al 2001;Schaffer et al 2005), thus suggesting unfavorable pharmacokinetics of oral administration protocols by sustained liver metabolism.…”

19F MRI of 3D CEM cells to study the effects of tocopherols and tocotrienols

“…However, previous studies associated vitamin E have been mostly focused on the role oftocopherol in breast cancer development [16]. Some authors demonstrated that 24 h exposure to 0-250 µM of -or -tocopherol and 0-250 µM of -tocopherol had effect on cell viability in highly malignant cells [17]. In particular for MCF-7 cells, the order of the concentrations required to induce 50% of cells viability was as follow: -tocopherol > -tocotrienol > -tocotrienol > -tocotrienol whereas for MDAMB-435 cells was -tocotrienol > -tocopherol > -tocotrienol > -tocotrienol [18].…”

Traditional oil palm (Elaeis guineensis jacq.) and its medicinal uses: A review

“…Studies have shown that tocotrienols fractions of palm oil were able to induce an inhibitory action on the human breast cancer cells, whereas the alpha-tocopherols were not able (Nesaretnam et al, 2004(Nesaretnam et al, , 2008McIntyre et al, 2000). Palm oil has been reported to be with wide range of protective properties against disease, aging as well as being modulators for cellular processes / functions where photo oxidative processes predominate by acting as scavengers of oxygen and peroxyl radicals (Van Rooyen et al, 2008).…”