The researchers, using blood and bone marrow cells from healthy newborns and adults, as well as leukemic cell lines, were able to determine the mechanism of DNA damage. The bioflavonoids, like the drugs VP16 and Dox, inhibit the action of an enzyme known as topoisomerase II (topo II), which helps to cleave apart and then rejoin strands of DNA, a process that is pivotal for various cell functions.
Leukemia can result when these normal DNA breaks are not properly reconnected, part of topo-II's mission.
MLL is a promiscuous gene. Once broken, it can reconnect with any of more than 40 other genes in a translocation, a process that involves an exchange of DNA between two chromosomes. Extensive recombinations usually cause cell death; but subtle translocations involving MLL can result in the rapid, uncontrolled cell division seen in leukemia.
Interestingly, cancerous cell lines that had developed resistance to drugs like VP16 and Dox were not susceptible to bioflavonoid DNA breaks.
Certain types of bioflavonoids, especially the flavonols, were more powerful topo-II inhibitors than others. For example, two different forms of quercetin, a dietary supplement, and fisetin, which is derived from herbs, were equal to VP16 in triggering MLL cleavage. Combinations of these substances demonstrated a cumulative effect.
Another group, the flavanones, found in citrus fruits, did not induce MLL cleavage.
"The public health message from this study is not yet clear," said Janet Rowley, M.D., Blum-Reise Distinguished Service Professor in the departments of medicine, molecular genetics & cell biology, a
Contact: John Easton
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University of Chicago Medical Center