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    A Combination of Three Synthetic Compounds Display Potent Antitumor Effects

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    Arnold_ku_0099M_16252_DATA_1.pdf (2.641Mb)
    Issue Date
    2018-12-31
    Author
    Arnold, Levi Kent
    Publisher
    University of Kansas
    Format
    46 pages
    Type
    Thesis
    Degree Level
    M.S.
    Discipline
    Cancer Biology
    Rights
    Copyright held by the author.
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    Abstract
    Patients suffering from head and neck squamous cell carcinoma (HNSCC) encounter low survival while managing current aggressive therapies that cause significant morbidity. Nutraceuticals are diet-derived compounds with few known side effects. However, limited antitumor efficacy has restricted their use for cancer therapy. In this work, we examined combined plant compounds, established a combination therapy that was more potent than its singular components, and delineated its mechanism of action. Curcumin is a yellow polyphenol that is derived from the rhizome of turmeric (Curcuma longa). It is known to influence multiple cellular processes. Likewise, harmine, a beta-carboline alkaloid found in Peganum harmala, and isovanillin, a phenolic aldehyde isomer of vanilla, have shown antitumor activity. We tested the antitumor efficacy of three formulation: GZ17-S (combined plant extracts from Arum palaestinum, R Peganum harmala and Curcuma longa); GZ17-05.00 (16 synthetic components of GZ17-S); and GZ17-06.02 (chemically synthesized curcumin, harmine and isovanillin). We tested the formulations on HNSCC progression. Specifically, we carried out in vitro studies on HNSCC proliferation, migration, invasion, angiogenesis, apoptosis, and macrophage viability and infiltration into the tumor. We demonstrated that GZ17-06.02 was most effective in attenuating in vitro parameters of HNSCC progression. Further, GZ17-06.02 potentiated the efficacy of cisplatin and radiation therapy. We demonstrate that GZ17-06.02 has multiple molecular targets including EGFR, ERK1/2, and AKT. We used molecular docking analyses to validate that GZ17-06.02 components bound at distinct binding sites on these targets. Finally, we demonstrated that GZ17-06.02 significantly inhibited the growth of established HNSCC cell lines, patient-derived xenografts, and murine syngeneic tumors (P<0.001). We demonstrated GZ17-06.02 as a highly effective plant extract combination for HNSCC. These studies provide rationale for clinical testing of GZ17-06.02 for HNSCC and other solid malignancies.
    URI
    http://hdl.handle.net/1808/30133
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    • KU Med Center Dissertations and Theses [464]
    • Theses [3828]

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    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
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    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
     

     

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