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    Identification of Novel Heat Shock Response Modulators for Experimental Anti-Melanoma Intervention

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    Author
    Davis, Angela Lee
    Issue Date
    2015
    Keywords
    Pharmaceutical Sciences
    Advisor
    Wondrak, Georg
    
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    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    Pharmacological induction of proteotoxic stress is rapidly emerging as a promising strategy for cancer cell-directed chemotherapeutic intervention. Due to the essential role of the cellular heat shock response in cytoprotection through the maintenance of proteostasis and suppression of apoptosis, small molecule heat shock protein (Hsp) inhibitors can be harnessed for targeted induction of cytotoxic effects in cancer cells. Recent research strongly suggests that melanoma is a malignant tumor amenable to therapeutic modulation of proteotoxic stress, particularly in situations where traditional chemotherapeutics and novel targeted therapies have failed. Based on this rationale, my graduate research has focused on the identification of redox-directed electrophilic pharmacophores capable of modulating the heat shock response for the therapeutic induction of proteotoxic stress targeting malignant human melanoma cells. The following specific aims were pursued: (1) to identify redox-directed heat shock response modulators active in malignant melanoma cells; (2) to explore melanoma cell directed activity of our lead heat shock response inducer, aurin (4-[bis(p-hydroxyphenyl)methylene]-2,5-cyclohexadien-1-one; CAS #143-74-8); and (3) to explore melanoma cell directed activity of our lead heat shock response antagonist, methylene blue (3,7-bis(dimethylamino)-phenothiazin-5-ium chloride; CAS#: 61-73-4). First, we demonstrate that the quinone methide, aurin, is a targeted Hsp90 inhibitor that induces apoptosis in human malignant melanoma cells but not in non-malignant human skin cells. Second, we have identified methylene blue as a functional antagonist of the global heat shock response which is active at the mRNA and protein levels, and have discovered that it sensitizes melanoma cells to the apoptogenic activity of the Hsp90 antagonist, geldanamycin. Taken together, these data suggest the feasibility of aurin and methylene blue as functional therapeutic heat shock response modulators targeting melanoma cells through pharmacological induction of proteotoxic stress.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Pharmaceutical Sciences
    Degree Grantor
    University of Arizona
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