The Indenoisoquinoline LMP517: A Novel Antitumor Agent Targeting both TOP1 and TOP2.

Abstract

The camptothecin derivatives topoisomerase I (TOP1) inhibitors, irinotecan and topotecan, are FDA approved for the treatment of colorectal, ovarian, lung and breast cancers. Because of the chemical instability of camptothecins, short plasma half-life, drug efflux by the multidrug-resistance ABC transporters, and the severe diarrhea produced by irinotecan, indenoisoquinoline TOP1 inhibitors (LMP400, LMP776, and LMP744), which overcome these limitations, have been developed and are in clinical development. Further modifications of the indenoisoquinolines led to the fluoroindenoisoquinolines, one of which, LMP517, is the focus of this study. LMP517 showed better antitumor activity than its parent compound LMP744 against H82 (small cell lung cancer) xenografts. Genetic analyses in DT40 cells showed a dual TOP1 and TOP2 signature with selectivity of LMP517 for DNA repair-deficient tyrosyl DNA phosphodiesterase 2 (TDP2)- and Ku70-knockout cells. RADAR assays revealed that LMP517, and to a lesser extent LMP744, induce TOP2 cleavage complexes (TOP2cc) in addition to TOP1ccs. Histone γH2AX detection showed that, unlike classical TOP1 inhibitors, LMP517 targets cells independently of their position in the cell cycle. Our study establishes LMP517 as a dual TOP1 and TOP2 inhibitor with therapeutic potential.

• Authors: Laetitia Marzi, Yilun Sun, Shar-Yin N Huang, Amy James, Simone Difilippantonio, Yves Pommier
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 19 Issue 8 Pg. 1589-1597 (08 2020) ISSN: 1538-8514 [Electronic] United States
• PMID: 32430490 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• H2AX protein, human
• Histones
• Indans
• Isoquinolines
• LMP517
• Neoplasm Proteins
• Recombinant Proteins
• Topoisomerase I Inhibitors
• Topoisomerase II Inhibitors
• Etoposide
• DNA Topoisomerases, Type I
• TOP1 protein, human
• DNA Topoisomerases, Type II
• Camptothecin

Topics

• Animals
• Camptothecin (pharmacology)
• Carcinoma, Small Cell (drug therapy)
• Cell Line, Tumor
• Chickens
• DNA Topoisomerases, Type I
• DNA Topoisomerases, Type II
• Etoposide (pharmacology)
• Female
• Histones (analysis)
• Humans
• Indans (pharmacology, therapeutic use)
• Isoquinolines (pharmacology, therapeutic use)
• Lung Neoplasms (drug therapy)
• Lymphoma (pathology, veterinary)
• Mice
• Mice, Nude
• Molecular Targeted Therapy
• Neoplasm Proteins (antagonists & inhibitors)
• Poultry Diseases (pathology)
• Random Allocation
• Recombinant Proteins (drug effects)
• Substrate Specificity
• Topoisomerase I Inhibitors (therapeutic use)
• Topoisomerase II Inhibitors (therapeutic use)
• Xenograft Model Antitumor Assays