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Biofactors. 2013 Jul-Aug;39(4):485-93. doi: 10.1002/biof.1089. Epub 2013 Jan 30.

Mitochondrial-dependent anticancer activity of δ-tocotrienol and its synthetic derivatives in HER-2/neu overexpressing breast adenocarcinoma cells.

Author information

1
Department of Internal Medicine, Section of Applied. Biochemistry. and Nutritional Science, University of Perugia, Italy.

Abstract

Anticancer activity and mitochondrial mechanism of the vitamin E form δ-tocotrienol (δ-T3) was investigated in HER-2/neu-overexpressing human SKBR3 and murine TUBO breast cancer cells. δ-T3 was confirmed to possess high cytotoxic and apoptotic activity in SKBR3 cells as compared with all natural forms of vitamin E and several synthetic forms that included novel derivatives with the same backbone of δ-T3 such as δ-tocotrienyl-succinyl amide (δ-T3AS) and the redox-active analogue δ-tocotrienyl amine (δ-T3NH2). As observed in the case of alpha-TOS, a prototypical anticancer drug derived from α-tocopherol, succinylation of δ-T3 enhanced citotoxicity and apoptotic activity of the vitamer. δ-T3 induced apoptosis of SKBR3 cells was associated with mitochondrial destabilization, energy failure, and unbalanced activity of stress/survival MAPKs, namely p38 and ERK1/2 pathways. An increased generation of ROS followed to such a series of early events. Enhanced activity of δ-T3 in this human carcinoma cell line was characterized by the sustained uptake and oxidative transformation to the quinone derivative δ-T3Q, thereby suggesting redox effects in SKBR3 mitochondria by this vitamer. Viability and uptake data show a different pattern of responses in TUBO cells with higher response to synthetic derivatives of δ-T3 than in SKBR3 cells. In conclusion, synthetic derivatives of δ-T3 with enhanced apoptotic activity in breast carcinoma cells are investigated for the first time in this study also describing mechanistic aspects of mitochondrial effects of δ-T3. Further investigation in preclinical models of HER2/neu-high breast adenocarcinoma is underway to identify other and more effective forms of VE in this type of cancer.

KEYWORDS:

HER-2/neu oncogene; breast cancer; mitochondria; tocotrienols; vitamin E

PMID:
23361894
DOI:
10.1002/biof.1089
[Indexed for MEDLINE]

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