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

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

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.

MeSH terms

  • Adenocarcinoma
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Breast Neoplasms
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Screening Assays, Antitumor
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Reactive Oxygen Species / metabolism
  • Receptor, ErbB-2 / metabolism*
  • Vitamin E / analogs & derivatives*
  • Vitamin E / pharmacology

Substances

  • Antineoplastic Agents
  • Reactive Oxygen Species
  • Vitamin E
  • tocotrienol, delta
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Extracellular Signal-Regulated MAP Kinases