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

Anticancer activity and mitochondrial mechanism of the vitamin E form [delta]-tocotrienol ([delta]-T3) was investigated in HER-2/neu-overexpressing human SKBR3 and murine TUBO breast cancer cells. [delta]-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 [delta]-T3 such as [delta]-tocotrienyl-succinyl amide ([delta]-T3AS) and the redox-active analogue [delta]-tocotrienyl amine ([delta]-T3NH2). As observed in the case of alpha-TOS, a prototypical anticancer drug derived from [alpha]-tocopherol, succinylation of [delta]-T3 enhanced citotoxicity and apoptotic activity of the vitamer. [delta]-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 [delta]-T3 in this human carcinoma cell line was characterized by the sustained uptake and oxidative transformation to the quinone derivative [delta]-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 [delta]-T3 than in SKBR3 cells. In conclusion, synthetic derivatives of [delta]-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 [delta]-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. [copy 2013 BioFactors, 39(4):485-493, 2013