KUKU

KU ScholarWorks

  • myKU
  • Email
  • Enroll & Pay
  • KU Directory
    • Login
    View Item 
    •   KU ScholarWorks
    • Dissertations and Theses
    • Dissertations
    • View Item
    •   KU ScholarWorks
    • Dissertations and Theses
    • Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Identifying Novel Inhibitors of Epithelial to Mesenchymal Transition (EMT) for Targeting Pancreatic Cancer Metastasis and Cancer Stem Cells

    Thumbnail
    View/Open
    Polireddy_ku_0099D_14319_DATA_1.pdf (4.799Mb)
    Issue Date
    2015-12-31
    Author
    Polireddy, Kishore
    Publisher
    University of Kansas
    Format
    169 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Pharmacology, Toxicology & Therapeutics
    Rights
    Copyright held by the author.
    Metadata
    Show full item record
    Abstract
    Pancreatic cancer is the fourth leading cause of cancer-related death in the United States, and it is expected to become the second-leading cause of cancer-related death by 2030. Currently, there are no early detection tests and most patients with localized disease have no recognizable symptoms. As a result, more than half of the patients with this disease are diagnosed at a stage where metastases have developed, for whom the overall 5-year survival is only 2%. Moreover, these tumors are highly enriched with a cancer stem cell (CSC) population (~1%), which is highly resistant to chemotherapeutic drugs, and therefore escapes chemotherapy and promotes tumor recurrence. Recent evidence suggests that epithelial to mesenchymal transition (EMT) is associated with metastasis, generation of CSCs, and treatment resistance in solid tumors including pancreatic cancer. Therefore, compounds inhibiting EMT hold the potential to reverse drug-resistance or inhibit metastasis and CSCs, and therefore could provide better treatment outcome for patients with pancreatic cancer. The overall goal of this dissertation is to investigate novel EMT inhibitors for targeting pancreatic cancer metastasis and CSCs. First we demonstrated in preclinical models that treatment with pharmacological doses of ascorbate resulted in inhibition of EMT, metastasis and CSCs. In addition, ascorbate decreased the expression of HDAC6, and inhibited activity of Sirt-2 by depleting NAD+ levels resulting in robustly increased α-tubulin acetylation in pancreatic cancer cells. Ascorbate mediated tubulin acetylation promoted α-tubulin polymerization and stabilization, mimicking the cellular outcomes of paclitaxel to inhibit cancer cell metastasis. Next, we investigated novel derivatives of the histone deacetylase (HDAC) inhibitors SAHA and MS-275, which are known EMT inhibitors. In an effort to increase efficacy and reduce toxicities of the HDAC inhibitors, we found that the novel synthetic compounds St-1 and St-3 potently inhibited pancreatic cancer cell proliferation and CSCs. St-1 has exhibited similar potency in HDAC inhibition compared to the parent compounds (SAHA and MS-275). Surprisingly, St-3 acted via totally different mechanisms from SAHA and MS-275. St-3 exhibited anti-tumor effects by blocking the interaction of human antigen R (HuR) with its target mRNAs. Finally, we established and performed a high throughput screening approach to identify inhibitiors of cancer cell EMT. 1-(benzylsulfonyl) indoline (BSI) was found to be a novel EMT inhibitor. BSI significantly inhibited pancreatic cancer cell migration invasion and CSCs. To enhance the efficacy of BSI, several analogues of BSI were tested for their activities on EMT and CSC inhibition. However, BSI analogues failed to show superior anti-migration or anti-CSC activities compare to BSI. In conclusion, this dissertation resulted in the identification of several novel EMT inhibitors, which can be tested further in preclinical studies for their anti-tumor efficacy.
    URI
    http://hdl.handle.net/1808/21926
    Collections
    • Dissertations [4475]
    • Pharmacy Dissertations and Theses [118]

    Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.


    We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.


    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

    Browse

    All of KU ScholarWorksCommunities & CollectionsThis Collection

    My Account

    LoginRegister

    Statistics

    View Usage Statistics

    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

    The University of Kansas
      Contact KU ScholarWorks
    Lawrence, KS | Maps
     
    • Academics
    • Admission
    • Alumni
    • Athletics
    • Campuses
    • Giving
    • Jobs

    The University of Kansas prohibits discrimination on the basis of race, color, ethnicity, religion, sex, national origin, age, ancestry, disability, status as a veteran, sexual orientation, marital status, parental status, gender identity, gender expression and genetic information in the University’s programs and activities. The following person has been designated to handle inquiries regarding the non-discrimination policies: Director of the Office of Institutional Opportunity and Access, IOA@ku.edu, 1246 W. Campus Road, Room 153A, Lawrence, KS, 66045, (785)864-6414, 711 TTY.

     Contact KU
    Lawrence, KS | Maps