Abstract

Estrogen receptor positive (ER+) breast cancer tends to respond to anti-estrogen agents such as Tamoxifen. Approximately 40% of ER+ breast cancer is resistant to these agents and those that initially respond often acquire resistance. Estrogen receptor negative (ER-) breast cancer remains largely unresponsive to these agents. It is therefore vital to discover drugs that are potent in both forms of breast cancer. Aminoflavone, (5-amino-2, 3-fluorophenyl)-6,8-difluoro-7-methyl-4H-l-benzopyran-4-one; AF; NSC 686288) and 5F203, (2-[-Amino-3-methy phenyl]-5-flurobenzothiazole) are novel anticancer candidate agents that display potent in vitro and in vivo anti-proliferative activity against select human tumor cells with a unique anticancer activity profile in the National Cancer Institute 60 cell line screen. AF and 5F203 activate the aryl hydrocarbon receptor (AhR) signaling pathway resulting in the transcription of genes such as those encoding cytochromes P450 1A1, 1A2 and 1B1. These cytochromes mediate the activity of AF and 5F203 by converting them into reactive intermediates that induce DNA damage in sensitive breast cancer cells. Previous reports indicate 5F203 shows activity in some ER- breast cancer cells including the MDA-MB-468 cell line and we have determined that AF inhibits the growth of MDA-MB-468 cells as well. We have also determined that AF induces S phase arrest with an accumulation of cells in sub G1 indicating the ability of AF to induce apoptosis. A number of chemotherapeutic agents and substances known to activate the AhR pathway and induce CYP1A1, increase intracellular reactive oxygen species (ROS) levels. Our preliminary studies indicated that AF and 5F203 alter intracellular ROS levels in sensitive cells. We hypothesize that AF and 5F203 modulate CYP-dependent ROS levels and mitogen activated protein kinase (MAPK) pathways resulting in the induction of DNA damage and apoptosis in sensitive breast cancer cells. In this project we have demonstrated that 1) ROS play a role in mediating the anticancer activity of AF and 5F 203 and determined that AF- and 5F 203- induced ROS modulation is CYP-linked, 2) AF and 5F203 induce oxidative DNA damage and subsequently activate caspase-dependent apoptosis and 3) AF and 5F203 modulate the activity of specific (MAPK) pathways to induce apoptosis in ER+ and ER-breast cancer cell lines. This project has defined the role of ROS in mediating the anticancer activity of 5F 203 and AF which are currently in Phase I clinical trials in the UK (administered in prodrug form) and US respectively.

LLU Discipline

Microbiology and Molecular Genetics

School

Graduate Studies

First Advisor

Eileen J. Brantley

Second Advisor

Carlos A. Casiano

Third Advisor

Willie L. Davis

Fourth Advisor

Daisy D. DeLeon

Fifth Advisor

Mark S. Johnson

Sixth Advisor

Ubaldo Soto

Seventh Advisor

Lawrence C. Sowers

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2008

Date (Title Page)

6-2008

Language

English

Library of Congress/MESH Subject Headings

Breast Neoplasms; DNA Damage -- drug effects; Amines -- analysis; Acetylcysteine -- pharmacology; Neoplasms -- immunology -- metabolism; Apoptosis -- drug effects; Antineoplastic Agents -- pharmacology; DNA, Neoplasm -- drug effects; Reactive Oxygen Species -- metabolism; Flavonoids -- antagonists & inhibitors -- pharmacology; Enzyme Activation

Type

Dissertation

Page Count

xv; 176

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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