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

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.

Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

“…The observation that δ-TT is associated with a significant proapoptotic effect in melanoma cells is in agreement with the reported antitumor activity of TTs (mainly δ-TT and γ-TT) in different types of tumors19333544.…”

Potential role of tocotrienols in the treatment and prevention of breast cancer

“…These same studies also confirmed that tocotrienol‐induced apoptosis was mediated independently of caspase 9 signaling . These results appeared to suggest that tocotrienol‐induced apoptosis was mediated by the extrinsic, but not the intrinsic apoptotic pathway in the highly malignant mouse +SA mammary tumor cell line , but is involved in human breast cancer cell lines . However, as +SA cells were found to contain nonfunctional death receptors, the exact mechanism involved in mediating the apoptotic effects of tocotrienol in these cells remained unclear .…”

Nutrigenomics of extra‐virgin olive oil: A review

“…The same type of considerations have been made on the quinone analogues of VOO phenolics . The mitochondrial‐dependent pro‐apoptotic activity of α‐T3 in HER2‐neu positive breast cancer cells and the corresponding in vivo anticancer activity are an example of these properties . Molecular players in this signaling of vitamin E‐related molecules include among the others, phospholipase A2, PKC isoforms and their corresponding phosphatases, pro‐survival and stress‐related MAPKs, and key regulatory components of cell cycle (reviewed in ).…”