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Full text of this paper is not available in the ETD Center. Copies may be available for inter-library loan from Kent State University or may be available for purchase from Proquest/UMI

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INFLUENCE OF GAMMA-SECRETASE INHIBITOR ON CYTOKINE-INDUCED APOPTOSIS IN BREAST CANCER CELL LINES

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2021, BS, Kent State University, College of Arts and Sciences / Department of Biological Sciences.
One of the evolutionary conserved pathways in multicellular organisms, Notch signaling pathway has been linked to proliferation and growth of different cancer types. Proteolytic cleavage of Notch receptors by the gamma-secretase complex (S3 cleavage) is a prerequisite for the canonical activation of Notch transcriptional potential and subsequent signaling. The targeted anti-cancer agent, Nirogacestat is a potent, small-molecule, selective, noncompetitive gamma-secretase inhibitor (GSI) with antitumor and antimetastatic activity in numerous cancers. It binds to gamma-secretase, blocking the proteolytic activation of Notch receptors, subsequently inhibiting the Notch signaling pathway and resulting in the induction of apoptosis in Notch over-expressing tumor cells. A recently developed dendritic cell-based vaccine against early breast cancer (ductal carcinoma in situ; DCIS) that generates strong Th1-dominated immunity against HER-2 has induced pathologic complete response (pCR) in about one-third of immunized individuals. In vitro studies suggested cytokines secreted by Th1 cells could be major contributors to the vaccine effects including induction of apoptosis and suppression of HER expression. We therefore investigated whether the principle Th1 cytokines (IFN-gamma and TNF-alpha) could act in concert with nirogacestat to suppress activity of breast cancer lines in vitro. Three different breast cancer cell lines: BT474, MDA-MB-231 and SKBR3 were incubated with Th1 cytokines, Nirogacestat, or both. It was found that combined treatment maximized metabolic suppression (Alamar Blue assay), as well as showed similar trend of cell death (Trypan Blue) and apoptosis (Annexin V/Propidium Iodide). These studies provide pre-clinical data that enhanced tumor kill is obtained by adding small molecule inhibitors of gamma-secretase and encourage the continued search for such additional agents that work cooperatively with Th1 cytokines, suggesting more efficacy of combination of targeted drug therapy with vaccination.
Gary Koski, Ph.D. (Advisor)
Elda Hegmann, Ph.D. (Committee Member)
Derek Damron, Ph.D. (Committee Member)
Bansidhar Datta, Ph.D. (Committee Member)
1 p.

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Citations

  • Bagale, A. (2021). INFLUENCE OF GAMMA-SECRETASE INHIBITOR ON CYTOKINE-INDUCED APOPTOSIS IN BREAST CANCER CELL LINES [Undergraduate thesis, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ksuhonors1620658488584152

    APA Style (7th edition)

  • Bagale, Abhishek. INFLUENCE OF GAMMA-SECRETASE INHIBITOR ON CYTOKINE-INDUCED APOPTOSIS IN BREAST CANCER CELL LINES. 2021. Kent State University, Undergraduate thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ksuhonors1620658488584152.

    MLA Style (8th edition)

  • Bagale, Abhishek. "INFLUENCE OF GAMMA-SECRETASE INHIBITOR ON CYTOKINE-INDUCED APOPTOSIS IN BREAST CANCER CELL LINES." Undergraduate thesis, Kent State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ksuhonors1620658488584152

    Chicago Manual of Style (17th edition)