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  • Redox Control of Apoptosis by Vitamin E Analogues

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    Freeman_2008_02Thesis.pdf (10.30Mb)
    Author
    Freeman, Ruth
    Primary Supervisor
    Jiri Neuzil
    Year published
    2008
    Metadata
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    Abstract
    Advances in diagnosis and treatment of cancer in recent years have resulted in reports showing that the overall long term trends of cancer mortality have been decreasing [1-3]. While this is good news, the prevalence of cancer is still at high rates within our community and around the world [1, 2, 4], which means that cancer research is an area that requires much research in order to maintain and hopefully accelerate the relative decline in cancer mortality. There are many potential mechanisms through which anti-cancer drugs work, and in recent times mitochondria have come into the spotlight as new and promising targets in ...
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    Advances in diagnosis and treatment of cancer in recent years have resulted in reports showing that the overall long term trends of cancer mortality have been decreasing [1-3]. While this is good news, the prevalence of cancer is still at high rates within our community and around the world [1, 2, 4], which means that cancer research is an area that requires much research in order to maintain and hopefully accelerate the relative decline in cancer mortality. There are many potential mechanisms through which anti-cancer drugs work, and in recent times mitochondria have come into the spotlight as new and promising targets in the destruction of cancer cells [5-8]. Mitochondria are vital for normal cellular functioning due to their role in energy production as well as being pivotal in the induction of apoptosis via the intrinsic or mitochondrial apoptotic pathway. A drug that has been shown to initiate apoptosis in cancer cells via mitochondria is α-tocopheryl succinate (α-TOS). α-TOS is an esterified form of vitamin E, with an apoptotic activity instead of acting as an anti-oxidant. While studies have been undertaken that shed light on the pathways used by α-TOS to initiate apoptosis [9-17], the precise mechanism that α-TOS utilises resulting in the production of reactive oxygen species (ROS), whose accumulation subsequently initiates apoptosis, is not well understood. Initially for this thesis, thioredoxin-1, a key anti-oxidant cellular protein, capable of preventing apoptosis via mechanisms associated with the mitochondrial pathway [18], was investigated to determine whether it could play a role in the induction of apoptosis by α-TOS. These studies revealed that while α-TOS induced apoptosis in malignant mesothelioma cell lines, with minimal effect on non-malignant mesothelial cells, Trx-1 did not appear to have any effect on the induction of apoptosis by α-TOS. To continue in this investigation the role of complex II, a component of the electron transport chain within the mitochondria, in α-TOS-induced apoptosis was examined. To study the potential role of complex II, cell lines originating from Chinese hamster lung fibroblasts were used. The parental B1 cells have a functional complex II, the B9 cells have a dysfunctional complex II because of a mutation in the SDHC (CybL) subunit, and B10 cells feature dysfunctional complex I. The B9 cells were also reconstituted with a functional human SDHC to form B9-SDHC cells. The cells with a dysfunctional complex II exhibited a significantly reduced response to apoptosis induction by α-TOS as well as a significant decrease in the production of ROS. This response was restored to the levels of the parental B1 cells when SDHC was reconstituted back in the B9 cells, showing that complex II has a significant role in the action of α-TOS. Human breast cancer MCF7 cells were used to study the effects of siRNA knock-down of complex II activity, and a significant decrease in apoptosis and ROS levels was again observed in response to α-TOS treatment. The B10 cells with dysfunctional complex I showed slightly lower levels of apoptosis and ROS generation in comparison to the parental B1 cells but this difference was not significant.
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    Thesis Type
    Thesis (PhD Doctorate)
    Degree Program
    Doctor of Philosophy (PhD)
    School
    School of Medical Science
    Item Access Status
    Public
    Note
    This thesis has been scanned from the print original.
    Subject
    Apoptosis
    Redox control
    Vitamin E
    Publication URI
    http://hdl.handle.net/10072/368101
    Collection
    • Theses - Higher Degree by Research

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