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  • Molecular Mechanisms of Breast Cancer Inhibition by Vitamin E Analogues

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    Wang_2010_02Thesis.pdf (1.697Mb)
    Author(s)
    Wang, Xiufang
    Primary Supervisor
    Neuzil, Jiri
    Other Supervisors
    Ralph, Steve
    Year published
    2010
    Metadata
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    Abstract
    Over-expression of the receptor tyrosine kinase erbB2 makes cancer cells resistant to apoptosis. α-Tocopheryl succinate (α-TOS), a redox-silent vitamin E (VE) analogue, has been shown to kill many different types of cancer cells. We tested whether α-TOS and several novel VE analogues kill breast cancer cells over-expressing the anti- apoptotic receptor protein erbB2 (HER2). Our experiments revealed that VE analogues caused comparable levels of apoptosis in breast cancer cells expressing different levels of erbB2. To extend our understanding of the molecular mechanisms of cell death triggered by VE analogues, we investigated ...
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    Over-expression of the receptor tyrosine kinase erbB2 makes cancer cells resistant to apoptosis. α-Tocopheryl succinate (α-TOS), a redox-silent vitamin E (VE) analogue, has been shown to kill many different types of cancer cells. We tested whether α-TOS and several novel VE analogues kill breast cancer cells over-expressing the anti- apoptotic receptor protein erbB2 (HER2). Our experiments revealed that VE analogues caused comparable levels of apoptosis in breast cancer cells expressing different levels of erbB2. To extend our understanding of the molecular mechanisms of cell death triggered by VE analogues, we investigated apoptotic pathways induced by the agents, one of which is the mitochondrial pathway. Generation of reactive oxygen species (ROS) preceded mitochondrial destabilization and execution of apoptosis, as evidenced by the anti-apoptotic effects of exogenous superoxide dismutase (SOD) and mitochondrially targeted coenzyme Q (MitoQ). Dissipation of the mitochondrial potential (ΔΨm) was followed by cytochrome c (Cyt c) and Smac/Diablo re-localization and caspase-dependent cleavage of death substrate. The other pathway studied was the survival (anti-apoptotic) Akt/NFκB signalling pathway. We document that α-TOS inhibited nuclear translocation of the subunit p65 of the transcriptional factor nuclear factor-κB (NFκB) in erbB2-over-expressing breast cancer cells, which is expected to result in inactivation of NFκB. A synergism of α- TOS and the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in apoptosis induction was confirmed in experiments with breast cancer cells with high and low expression of erbB2. To verify the efficacy of VE analogues in killing cancer cells in vivo, we also used the FVB/N c-neu transgenic mice with spontaneous breast carcinomas (high erbB2) and the human breast cancer MCF7 xenograft model (low erbB2) to investigate the effect of α-TOS on cancer progression. We show that α-TOS significantly inhibited tumour growth compared to the controls in both animal models.
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    Thesis Type
    Thesis (PhD Doctorate)
    Degree Program
    Doctor of Philosophy (PhD)
    School
    School of Medical Science
    DOI
    https://doi.org/10.25904/1912/2164
    Copyright Statement
    The author owns the copyright in this thesis, unless stated otherwise.
    Item Access Status
    Public
    Note
    The published papers in the appendix are not included here.
    Subject
    Breast cancer
    Vitamin E analogue
    a-Tocopheryl succinate
    Receptor tyrosine kinase
    Publication URI
    http://hdl.handle.net/10072/367116
    Collection
    • Theses - Higher Degree by Research

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