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First published on June 23, 2006; DOI: 10.1124/mol.106.024372

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Received for publication March 15, 2006.
Revised June 21, 2006.
Accepted for publication June 23, 2006.

Bisindenoisoquinoline NSC 727357, a DNA intercalator and topoisomerase inhibitor with antitumor activity

Smitha Antony 1, Keli K Agama 1, Ze-Hong Miao 1, Melinda Hollingshead 2, Susan L Holbeck 3, Mollie H Wright 4, Lyuba Varticovski 4, Muthukaman Nagarajan 5, Andrew Morrell 5, Mark Cushman 5, Yves G. Pommier 1*

1 National Cancer Institute, National Institutes of Health 2 Biological Testing Branch, National Cancer Institute, NIH 3 Information Technology Branch, National Cancer Institute, NIH 4 Laboratory of Human Carcinogenesis, NCI, NIH 5 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University

* Address correspondence to: E-mail: pommier{at}nih.gov

Abstract

Indenoisoquinolines are topoisomerase I (Top1) inhibitors developed to overcome some of the limitations of camptothecins and expand their anticancer spectrum. NSC 727357 is a novel dimeric indenoisoquinoline derivative with potent antiproliferative activity in the NCI-60 cell line panel, promising hollow fiber activity (score = 32) and activity against xenografts. Submicromolar concentrations of the bisindenoisoquinoline NSC 727357 induce Top1 cleavage complexes at specific sites in biochemical assays. At higher concentrations an inhibition of Top1 catalytic activity and DNA intercalation are observed. NSC 727357 also induces a limited number of Top2-DNA cleavage complexes. In contrast to the effect of other Top1 inhibitors, cells treated with the bisindenoisoquinoline NSC 727357 show an arrest of cell cycle progression in G1 with no significant inhibition of DNA synthesis following a short exposure to the drug. Moreover, unlike camptothecin and the indenoisoquinoline MJ-III-65 (NSC 706744), the cytotoxicity of bisindenoisoquinoline NSC 727357 is only partially dependent on Top1 and p53, indicating that this drug has additional targets besides Top1 and Top2.


Key words: DNA intercalation, Topoisomerases


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