We have identified a small library of novel substituted 9-aminoacridine derivatives that inhibit cell proliferation of pancreatic cancer cell lines by inducing apoptosis [Goodell, J.R. et al., 2008. J. Med. Chem. 51, 179-182.]. To further investigate their antiproliferative activities, we have assessed the antiproliferative activity of these acridine-based compounds against several pancreatic cancer cell lines. All four compounds used in this study inhibited the proliferation of pancreatic cancer cell lines in vitro. In addition, we have employed a xenograft tumor model and found that these compounds also inhibit the proliferation of pancreatic cancer in vivo. In light of the potential importance of the anticancer activity of these acridine-based compounds, we have conducted a series of biochemical assays to determine the effect of these compounds on human topoisomerase II. Unlike amsacrine, these compounds do not poison topoisomerase II. Similar to amsacrine, however, these compounds intercalate into DNA in a way that they would alter the apparent topology of the DNA substrate. Thus, inhibition of the relaxation activity of topoisomerase II by these compounds has been reexamined using a DNA strand passage assay. We have found that these compounds, indeed, inhibit the catalytic activity of topoisomerase II. Thus, these novel acridine-based compounds with anti-pancreatic cancer activity are catalytic inhibitors, not poisons, of human topoisomerase II.
Bibliographical noteFunding Information:
This work was in part supported by a Faculty Research Development Grant from the University of Minnesota Academic Heath Center (to DMF and HH), a Pilot Project Grant from the Specialized Program in Research Excellence grant P20 CA101955 (to HH), a Specialized Program in Research Excellence grant P50 CA102701 from the NCI (to DDB), a Partnership grant from the State of Minnesota (to DDB and DMF), the Mayo Foundation (to DDB), and a fund from the University of Minnesota Medical School (to HH).
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- Acridine derivative
- Anticancer drug
- Catalytic inhibitor
- DNA intercalation