Degree Name
PhD (Doctor of Philosophy)
Program
Biomedical Sciences
Date of Award
12-2016
Committee Chair or Co-Chairs
Victoria Palau
Committee Members
Sam Harirforoosh, Zachary Walls, Gary Wright, Koyamangalath Krishnan
Abstract
Flavonoids are polyphenolic secondary metabolites found in plants that have bioactive properties including antiviral, antioxidant, and anticancer. Two isomeric flavone were extracted from Gnaphalium elegans and Achyrocline bogotensis, plants used by the people from the Andean region of South America as remedies for cancer. 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5, 7–dihydroxy- 3, 6, 8 trimethoxy flavone/ flavone A) and 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3, 5–dihydroxy-6, 7, 8–trimethoxy flavone/ flavone B) have shown antineoplastic activity against colon cancer cell lines dependent upon their differentiation status. Pharmacokinetic studies reported herein were used to determine dosing for antitumor assays, as well as determine target tissue concentration. These included the development of methods to extract the flavones from plasma or colon tissue and reverse phase high performance liquid chromatography methods for quantification. Quantification methods were linear (r2 ≥ 0.99) with plasma calibration curves ranging from 250 - 2,500 ng/mL and 2,500 - 100,000 ng/mL for both flavones and colon calibration curves ranging from 250 – 100,000 ng/g (flavone A) and 1,000-25,000 ng/g (flavone B). Intravenous administration of a 20 mg/kg dose in rats yielded half-lives of 83.68 ± 56.61 and 107.45 ± 53.31 minutes with clearance values of 12.99 ± 13.78 and 80.79 ± 35.06 mL/min/kg for flavones A and B, respectively. Analysis of colon tissue yielded concentrations of 1639 ± 601 ng/g (flavone A) and 5975 ± 2480 ng/g (flavone B), suggesting both may be good candidate for individual or adjunct therapy for colon cancer due to distribution to the target tissue. Preliminary studies in colon cancer cells CaCo 2 and HCT 116 using either flavone in combination with 5-fluorouracil (5-FU) suggested synergistic activity of these compounds. The combination treatment increased induction of apoptosis by enhancing the DNA damaging mechanism of 5-FU. In vivo, preliminary xenograft experiments using HCT 116 cells showed smaller tumors in mice dosed with flavone B as compared to the 5-FU or combination treatment. Further experiments are warranted to confirm these observations.
Document Type
Dissertation - unrestricted
Recommended Citation
Whitted, Crystal L., "Pharmacokinetics, Tissue Distribution, Synergistic Activity, and Antitumor Activity of Two Isomeric Flavones" (2016). Electronic Theses and Dissertations. Paper 3167. https://dc.etsu.edu/etd/3167
Copyright
Copyright by the authors.
Included in
Biology Commons, Cancer Biology Commons, Molecular Biology Commons, Pharmacology Commons