Abstract

Bioflavonoids are potent topoisomerase II poisons and are believed to be chemopreventative in adults. However, they have also been implicated in the initiation of acute myeloid leukemia's (AMLs) in utero. The overall goal of this proposal is to further define the mechanism by which bioflavonoids alter the catalytic activity of human topoisomerase II and their potential role in the initiation of carcinogenesis.
The specific aims for this proposal are to: (1) Delineate the mechanism by which bioflavonoids alter the catalytic function of human type II topoisomerases via in vitro enzymological studies that are used to examine DNA cleavage and ligation. Mutagenesis and NMR studies will be employed to define the site of interaction of bioflavonoids on the enzyme. (2) Determine the role of topoisomerase II alpha and beta in mediating the cytotoxic and genotoxic effects of bioflavonoids in human cells by using siRNA. The role of each isoform in the initiation of bioflavonoid-induced MIL gene translocations in cultured human cells will be examined via cloning and PCR approaches. This project will further our understanding of the chemopreventative and cytotoxic properties of bioflavonoids and potentially lead to the utilization of these compounds as chemotherpeutic agents. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31GM078744-02
Application #
7282436
Study Section
Minority Programs Review Committee (MPRC)
Program Officer
Toliver, Adolphus
Project Start
2006-09-01
Project End
2008-03-31
Budget Start
2007-09-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2007
Total Cost
$17,948
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212

  Publications

Bandele, Omari J; Osheroff, Neil (2009) Cleavage of plasmid DNA by eukaryotic topoisomerase II. Methods Mol Biol 582:39-47
Bandele, Omari J; Clawson, Sara J; Osheroff, Neil (2008) Dietary polyphenols as topoisomerase II poisons: B ring and C ring substituents determine the mechanism of enzyme-mediated DNA cleavage enhancement. Chem Res Toxicol 21:1253-60
Bandele, Omari J; Osheroff, Neil (2008) The efficacy of topoisomerase II-targeted anticancer agents reflects the persistence of drug-induced cleavage complexes in cells. Biochemistry 47:11900-8
Bandele, Omari J; Osheroff, Neil (2008) (-)-Epigallocatechin gallate, a major constituent of green tea, poisons human type II topoisomerases. Chem Res Toxicol 21:936-43
Bandele, Omari J; Osheroff, Neil (2007) Bioflavonoids as poisons of human topoisomerase II alpha and II beta. Biochemistry 46:6097-108