Novel acridine-based compounds that exhibit an anti-pancreatic cancer activity are catalytic inhibitors of human topoisomerase II

Lisa M. Oppegard, Andrei V. Ougolkov, Doris N. Luchini, Renee A. Schoon, John R. Goodell, Harneet Kaur, Daniel D. Billadeau, David M Ferguson, Hiroshi Hiasa

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)223-229
Number of pages7
JournalEuropean Journal of Pharmacology
Volume602
Issue number2-3
DOIs
StatePublished - Jan 14 2009

Fingerprint

Topoisomerase II Inhibitors
Acridines
Type II DNA Topoisomerase
Pancreatic Neoplasms
Amsacrine
Poisons
Cell Line
DNA
Aminacrine
Heterografts
Libraries
Cell Proliferation
Apoptosis
Neoplasms

Keywords

  • Acridine derivative
  • Anticancer drug
  • Cancer
  • Catalytic inhibitor
  • DNA intercalation
  • Topoisomerase

Cite this

Novel acridine-based compounds that exhibit an anti-pancreatic cancer activity are catalytic inhibitors of human topoisomerase II. / Oppegard, Lisa M.; Ougolkov, Andrei V.; Luchini, Doris N.; Schoon, Renee A.; Goodell, John R.; Kaur, Harneet; Billadeau, Daniel D.; Ferguson, David M; Hiasa, Hiroshi.

In: European Journal of Pharmacology, Vol. 602, No. 2-3, 14.01.2009, p. 223-229.

Research output: Contribution to journalArticle

Oppegard, Lisa M. ; Ougolkov, Andrei V. ; Luchini, Doris N. ; Schoon, Renee A. ; Goodell, John R. ; Kaur, Harneet ; Billadeau, Daniel D. ; Ferguson, David M ; Hiasa, Hiroshi. / Novel acridine-based compounds that exhibit an anti-pancreatic cancer activity are catalytic inhibitors of human topoisomerase II. In: European Journal of Pharmacology. 2009 ; Vol. 602, No. 2-3. pp. 223-229.
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AU - Schoon, Renee A.

AU - Goodell, John R.

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AB - 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.

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