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Optimization of Synthetic Flavonolignans to Target Embryonic Signaling in Metastatic Ovarian and Colon Cancer.

Amawi, Haneen
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1510514631544003

Abstract Details

2017, Doctor of Philosophy, University of Toledo, Experimental Therapeutics.
This thesis work reports the synthesis and anticancer activity evaluation of twelve novel silybin analogues designed using a novel ring disjunctive-based natural product lead (RDNPL) optimization approach. The twelve synthetic novel derivatives (HM015a- HM015k) were screened for their cytotoxicities against several cancerous cell lines and normal epithelial cells. HM015k or 15k, was selected as a leading compound where it induced potent and selective cytotoxicity against both ovarian (OV2008, A2780) and colon (HCT116, S, and LOVO) cancer cell lines. The cytotoxicity of 15k was further confirmed and 15k treatment induced significant inhibition in the cancer cells proliferation with time and their colony formation rates. Mechanistic studies indicated that the antiproliferative efficacy of 15k was mediated through significant induction of cell cycle arrest, oxidative stress, and apoptosis. Furthermore, 15k inhibited cellular microtubules dynamic and assembly by binding to tubulin and inhibiting its levels and function in both colon and ovarian cancer cells. The compound 15k reversed cancer cells migration and invasion potentials. Further, the 15k treatment induced significant reversal in EMT morphology and markers with significant downregulation in Wnt/ ß-catenin signaling in both cancers. Finally, 15k was safe in zebrafish in vivo model at concentrations up to 10 µM and induced no cardiac or morphological toxicities.
Tiwari Amit (Committee Chair)
Hassoun Ezdihar (Committee Member)
Sari Youssef (Committee Member)
Shah Zahoor (Committee Member)
376 p.
Pharmacology
Ovarian cancer; Colon cancer; silybin; silymarin; metastasis; apoptosis; epithelial - mesenchymal transition; zebrafish; drug discovery;

Recommended Citations

Citations

  • Amawi, H. (2017). Optimization of Synthetic Flavonolignans to Target Embryonic Signaling in Metastatic Ovarian and Colon Cancer. [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1510514631544003

    APA Style (7th edition)

  • Amawi, Haneen. Optimization of Synthetic Flavonolignans to Target Embryonic Signaling in Metastatic Ovarian and Colon Cancer. 2017. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1510514631544003.

    MLA Style (8th edition)

  • Amawi, Haneen. "Optimization of Synthetic Flavonolignans to Target Embryonic Signaling in Metastatic Ovarian and Colon Cancer." Doctoral dissertation, University of Toledo, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1510514631544003

    Chicago Manual of Style (17th edition)

toledo1510514631544003
828
© 2017, some rights reserved.Creative Commons License Optimization of Synthetic Flavonolignans to Target Embryonic Signaling in Metastatic Ovarian and Colon Cancer. by Haneen Amawi is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Toledo and OhioLINK.