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. 2013 Apr;46(2):203-13.
doi: 10.1111/cpr.12014.

Tocotrienols Promote Apoptosis in Human Breast Cancer Cells by Inducing poly(ADP-ribose) Polymerase Cleavage and Inhibiting Nuclear Factor kappa-B Activity

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Tocotrienols Promote Apoptosis in Human Breast Cancer Cells by Inducing poly(ADP-ribose) Polymerase Cleavage and Inhibiting Nuclear Factor kappa-B Activity

R Loganathan et al. Cell Prolif. .
Free PMC article

Abstract

Objectives: Tocotrienols and tocopherols are members of the vitamin E family, with similar structures; however, only tocotrienols have been reported to achieve potent anti-cancer effects. The study described here has evaluated anti-cancer activity of vitamin E to elucidate mechanisms of cell death, using human breast cancer cells.

Materials and methods: Anti-cancer activity of a tocotrienol-rich fraction (TRF) and a tocotrienol-enriched fraction (TEF) isolated from palm oil, as well as pure vitamin E analogues (α-tocopherol, α-, δ- and γ-tocotrienols) were studied using highly aggressive triple negative MDA-MB-231 cells and oestrogen-dependent MCF-7 cells, both of human breast cancer cell lines. Cell population growth was evaluated using a Coulter particle counter. Cell death mechanism, poly(ADP-ribose) polymerase cleavage and levels of NF-κB were determined using commercial ELISA kits.

Results: Tocotrienols exerted potent anti-proliferative effects on both types of cell by inducing apoptosis, the underlying mechanism of cell death being ascertained using respective IC50 concentrations of all test compounds. There was marked induction of apoptosis in both cell lines by tocotrienols compared to treatment with Paclitaxel, which was used as positive control. This activity was found to be associated with cleavage of poly(ADP-ribose) polymerase (a DNA repair protein), demonstrating involvement of the apoptotic cell death signalling pathway. Tocotrienols also inhibited expression of nuclear factor kappa-B (NF-κB), which in turn can increase sensitivity of cancer cells to apoptosis.

Conclusion: Tocotrienols induced anti-proliferative and apoptotic effects in association with DNA fragmentation, poly(ADP-ribose) polymerase cleavage and NF-κB inhibition in the two human breast cancer cell lines.

Figures

Figure 1
Figure 1
Antiproliferative activity of palm vitamin E on human breast cancer cells. The (a) MDAâMBâ231 and (b) MCFâ7 human breast cancer cells were coâcultured with increasing concentrations (0â20 Îg/ml) of the test compounds at 37ÂÂC in a humidified 5% CO 2 incubator for 72Âh. The viable cells were assayed using Coulter Particle Counter. Points indicate triplicate the mean of triplicate counts/well  STD for triplicates in each treatment group. All values are significantly different (PÂ<Â0.05) from the control group except for *.
Figure 2
Figure 2
Apoptotic effect of vitamin E on human breast cancer cells treated at IC50 concentrations. The apoptotic effect of of vitamin E (IC 50 concentrations) on (i) MDAâMBâ231 and (ii) MCFâ7 cells at after a) 24Âh and b) 48Âh. Results are shown as the mean  STD from triplicate cultures. (*) values are significantly different from the control group, PÂ<Â0.05 (oneâway ANOVA).
Figure 3
Figure 3
Mode of cell death of human breast cancer cells treated with vitamin E isomers for 72Âh. The mode of cell death induced in (a) MDAâMBâ231 and (b) MCFâ7 cells coâcultured with various treatments of vitamin E (10ÂÎg/ml) for 72Âh. Results are shown as the mean  STD from triplicate cultures. (*) values are significantly different from the control group, PÂ<Â0.05 (oneâway ANOVA).
Figure 4
Figure 4
Apoptosis induction by PARP cleavage following Vitamin E treatment. The (a) MDAâMBâ231 and (b) MCFâ7 human breast cancer cells were coâcultured for 24Âh with 10ÂÎg/ml of various isomers of vitamin E. These cells were briefly exposed to 1Ânm TNFâÎ for 30Âmin. The PARP cleavage activity was determined using ELISA method. Results are shown as the mean  STD from duplicate cultures. (*) values are significantly different from the control group, PÂ<Â0.05 (oneâway ANOVA).
Figure 5
Figure 5
Apoptosis induction by PARP cleavage with Vitamin E treatment. The (a) MDAâMBâ231 and (b) MCFâ7 human breast cancer cells were coâcultured for 24Âh with 10ÂÎg/ml of various isomers of vitamin E. These cells were briefly exposed to 1Ânm TNFâÎ for 30Âmin. The PARP cleavage activity was determined using the western blotting method.
Figure 6
Figure 6
Effect of Vitamin E on TNFâÎ activated NFâÎB expression. The (a) MDAâMBâ231 and (b) MCFâ7 human breast cancer cells were coâcultured for 24Âh with 10ÂÎg/ml of various isomers of vitamin E. These cells were briefly exposed to 1ÂnM TNFâÎ for 30Âmin. Nuclear extracts were prepared and analysed for NFâÎB expression by ELISA. Results are shown as the meanÂÂÂSTD from duplicate cultures. (*) values are significantly different from the control +TNF group, (#) values are significantly different from the control group, pÂ<Â0.05 (oneâway ANOVA).

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