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Robinson Dissertation.pdf (45.88 MB)

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Synthesis and Evaluation of Inducers of Methuotic Cell Death and Preliminary Identification of Their Cellular Targets in Glioblastoma Cells

Robinson, Michael W
http://rave.ohiolink.edu/etdc/view?acc_num=mco1372430209

Abstract Details

2013, Doctor of Philosophy (PhD), University of Toledo, College of Medicine.
The overall goal in cancer therapeutics is to do induce cell death in the tumor cells. While many classical anticancer drugs have different targets, they generally induce cell death by stimulating signaling pathways that ultimately activate apoptosis. Unfortunately, many genetic alterations that help drive the progression of a tumor cell also lead to apoptosis resistance. Thus, cancers are often treated with drugs to which they are inherently resistant. In order to circumvent this problem, there is a strong interest in identifying new forms of non-apoptotic cell death, with the goal of developing therapies that can activate these forms of cell death. Our lab has recently identified a form of non-apoptotic cell death called methuosis, characterized by hyperstimulated macropinocytosis and disrupted trafficking of these vesicles to the lysosome. These vesicles overwhelm the cytoplasm, disrupt cellular metabolism, and compromise membrane integrity, resulting in cell death. Methuosis was originally characterized in glioblastoma cell culture by overexpression of activated Ras or Rac GTPases. However, our lab recently identified a class of small molecules that induce methuosis in cancer cells, providing a potential way to induce this form of cell death therapeutically. This dissertation describes studies aimed to further understand the molecules that induce methuosis. First, the structure activity relationships of compounds that induce methuosis were evaluated, resulting in the identification of our lead compound, MOMIPP. Next, we sought to identify the cellular targets of MOMIPP that lead to methuosis induction. Accordingly, various chemical tools were synthesized and used to identify MOMIPP target proteins. Ultimately, two proteins that specifically bind MOMIPP were identified as candidates for methuosis-triggering activity. These await further characterization to confirm their relationship to methuosis and cell death.
William Maltese, PhD (Committee Chair)
Paul Erhardt, PhD (Committee Member)
Kenneth Hensley, PhD (Committee Member)
Jean Overmeyer, PhD (Committee Member)
James Slama, PhD (Committee Member)
Kana Yamamoto, PhD (Committee Member)
305 p.
Biochemistry; Chemistry; Oncology; Organic Chemistry
cancer therapeutics; chemical biology; biochemistry; target identification; photoaffinity labeling; chalcone; synthetic medicinal chemistry; apoptosis; non-apoptotic cell death; methuosis; cancer; glioblastoma

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Citations

  • Robinson, M. W. (2013). Synthesis and Evaluation of Inducers of Methuotic Cell Death and Preliminary Identification of Their Cellular Targets in Glioblastoma Cells [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1372430209

    APA Style (7th edition)

  • Robinson, Michael. Synthesis and Evaluation of Inducers of Methuotic Cell Death and Preliminary Identification of Their Cellular Targets in Glioblastoma Cells. 2013. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1372430209.

    MLA Style (8th edition)

  • Robinson, Michael. "Synthesis and Evaluation of Inducers of Methuotic Cell Death and Preliminary Identification of Their Cellular Targets in Glioblastoma Cells." Doctoral dissertation, University of Toledo, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=mco1372430209

    Chicago Manual of Style (17th edition)

mco1372430209
286
© 2013, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.