Novel Fluoroindenoisoquinoline Non-Camptothecin Topoisomerase I Inhibitors

• Published in: Molecular cancer therapeutics Vol. 17; no. 8; pp. 1694 - 1704
• Main Authors: Marzi, Laetitia, Agama, Keli, Murai, Junko, Difilippantonio, Simone, James, Amy, Peer, Cody J, Figg, William D, Beck, Daniel, Elsayed, Mohamed S A, Cushman, Mark, Pommier, Yves
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.08.2018
• Subjects: Animals; Anticancer properties; Antitumor activity; Antitumor agents; Bioinformatics; Camptothecin; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Camptothecin - therapeutic use; Cancer; Colon; Deoxyribonucleic acid; Derivatives; DNA; DNA damage; DNA topoisomerase; Drugs; Female; Fluorine; Genomic analysis; Histone H2A; Humans; Inhibitors; Irinotecan; Leukemia; Lung cancer; Mice; Mice, Nude; Organic chemistry; Phosphorylation; Small cell lung carcinoma; Stability; Topoisomerase I Inhibitors - pharmacology; Topoisomerase I Inhibitors - therapeutic use; Topotecan; Xenografts; Xenotransplantation
• ISSN: 1535-7163; 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.mct-18-0028

Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of the plant alkaloid, camptothecin. The indenoisoquinolines LMP400, LMP744, and LMP776 are novel noncamptothecin TOP1 inhibitors in clinical trial, which overcome the limitations of camptothecins. To further improve metabolic stability, their methoxy groups have been replaced by fluorine, as in the fluoroindenoisoquinolines NSC 781517 (LMP517), NSC 779135 (LMP135), and NSC 779134 (LMP134). We tested the induction and stability of TOP1 cleavage complexes (TOP1cc), and the induction and persistence of DNA damage measured by histone H2AX phosphorylation (γH2AX) compared with their parent compounds LMP744 and LMP776 in leukemia CCRF-CEM and colon carcinoma HCT116 cells. The fluoroindenoisoquinolines induced TOP1cc and γH2AX at nanomolar concentrations, and at higher levels than the parent indenoisoquinolines. The fluoroindenoisoquinoline LMP135 showed greater antitumor activity than topotecan in small-cell lung cancer cell H82 xenografts. It was also more potent than topotecan in the NCI-60 cancer cell line panel. Bioinformatics tools (http://discover.nci.nih.gov/cellminercdb) were used to investigate the following: (i) the correlations of fluoroindenoisoquinolines activity with other drugs, and (ii) genomic determinants of response in the NCI-60. The activity of the fluoroindenoisoquinolines was mostly correlated with camptothecin derivatives and the parent indenoisoquinolines, consistent with TOP1 targeting. Genomic analyses and activity assays in CCRF-CEM -deleted cells showed that expression is a dominant determinant of response to LMP135. This study shows the potential value of the fluoroindenoisoquinolines for further development as novel anticancer agents targeting TOP1. .