title: Novel indenoisoquinolines NSC 725776 and NSC 724998 produce persistent topoisomerase I cleavage complexes and overcome multidrug resistance.
abstract: Camptothecin (CPT) derivatives are effective anticancer drugs, especially against solid tumors. As CPTs are chemically unstable and have clinical limitations, we have synthesized indenoisoquinolines as novel topoisomerase I (Top1) inhibitors. We presently report two indenoisoquinoline derivatives, NSC 725776 and NSC 724998, which have been selected for therapeutic development. Both are potent Top1 inhibitors and induce Top1 cleavage at unique genomic positions compared with CPT. Consistent with Top1 poisoning, protein-linked DNA breaks were detected in cells treated with NSC 725776 and NSC 724998 at nanomolar concentrations. Those drug-induced protein-linked DNA breaks persisted longer after drug removal than those produced by CPT. Studies in human cells in culture show that NSC 725776 and NSC 724998 exert antiproliferative activity at submicromolar concentrations. Furthermore, NSC 725776 and NSC 724998 show cross-resistance in cells deficient or silenced for Top1, which is consistent with their selective Top1 targeting. Similar to other known Top1 inhibitors, NSC 725776-treated and NSC 724998-treated cells show an arrest of cell cycle progression in both S and G(2)-M and a dependence on functional p53 for their cytotoxicity. Dose-dependent gamma-H2AX foci formation was readily observed in cells treated with NSC 725776 and NSC 724998. These gamma-H2AX foci were detectable at pharmacologically relevant doses for up to 24 h and thus could be used as biomarkers for clinical trials (phase 0).
authors.affiliation: Laboratory of Molecular Pharmacology, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA.
authors.forename: Smitha
authors.initials: S
authors.lastname: Antony
authors.forename: Keli K
authors.initials: KK
authors.lastname: Agama
authors.forename: Ze-Hong
authors.initials: ZH
authors.lastname: Miao
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Takagi
authors.forename: Mollie H
authors.initials: MH
authors.lastname: Wright
authors.forename: Ana I
authors.initials: AI
authors.lastname: Robles
authors.forename: Lyuba
authors.initials: L
authors.lastname: Varticovski
authors.forename: Muthukaman
authors.initials: M
authors.lastname: Nagarajan
authors.forename: Andrew
authors.initials: A
authors.lastname: Morrell
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007192:Indenes; D007546:Isoquinolines / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000502:physiology; D059004:Topoisomerase I Inhibitors
chemical_list: C415158:6-(3-(2-hydroxyethyl)amino-1-propyl)-5,6-dihydro-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno(1,2-)isoquinoline; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D052117:Benzodioxoles; D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D006657:Histones; D007192:Indenes; D007546:Isoquinolines; C553898:NSC 724998; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I