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Mitochondrial‐dependent anticancer activity of δ‐tocotrienol and its synthetic derivatives in HER‐2/neu overexpressing breast adenocarcinoma cells
Author(s) -
Viola Valentina,
Ciffolilli Silvia,
Legnaioli Silvia,
Piroddi Marta,
Betti Michele,
Mazzini Francesco,
Pierpaoli Elisa,
Provinciali Mauro,
Galli Francesco
Publication year - 2013
Publication title -
biofactors
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.204
H-Index - 94
eISSN - 1872-8081
pISSN - 0951-6433
DOI - 10.1002/biof.1089
Subject(s) - tocotrienol , chemistry , pharmacology , cancer research , medicine , biochemistry , tocopherol , antioxidant , vitamin e
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. © 2013 BioFactors, 39(4):485–493, 2013