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The DNA-Binding Polyamine Moiety in the Vectorized DNA

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The DNA-Binding Polyamine Moiety in the Vectorized DNA Published OnlineFirst June 13, 2017; DOI: 10.1158/1535-7163.MCT-16-0767 Small Molecule Therapeutics Molecular Cancer Therapeutics The DNA-Binding Polyamine Moiety in the Vectorized DNA Topoisomerase II Inhibitor F14512 Alters Reparability of the Consequent Enzyme-Linked DNA Double-Strand Breaks Oriane Bombarde1, Florence Larminat1, Dennis Gomez1, Philippe Frit1, Carine Racca1, Bruno Gomes2, Nicolas Guilbaud2, and Patrick Calsou1,3 Abstract Poisons of topoisomerase II (TOP2) kill cancer cells by pre- being more cytotoxic, F14512 is less efficient than etoposide at venting religation of intermediate DNA breaks during the enzy- producing TOP2a cleavage-complex (TOP2acc) in cells. Finally, matic process and thus by accumulating enzyme–drug–DNA we report that compared with TOP2acc mediated by etoposide, complexes called TOP2 cleavage-complex (TOP2cc). F14512 is those generated by F14512 persist longer in the genome, are not a highly cytotoxic polyamine-vectorized TOP2 inhibitor derived dependent on TDP2 for cleaning break ends from TOP2a, are from etoposide and currently in clinical trials. It was shown in vitro channeled to a larger extent to resection-based repair processes that F14512 has acquired DNA-binding properties and that the relying on CtIP and BRCA1 and promote RAD51 recruitment to stability of TOP2cc was strongly increased. Paradoxically, at damaged chromatin. In addition to the addressing of F14512 to equitoxic concentrations in cells, F14512 induced less DNA the polyamine transport system, the properties uncovered here breaks than etoposide. Here, we directly compared etoposide and would be particularly valuable for a therapeutic usage of this new F14512 for their rates of TOP2cc production and resolution in anticancer compound. More generally, the concept of increasing human cells. We report that targeting of TOP2a and not TOP2b drug cytotoxicity by switching the repair mode of the induced impacts cell killing by F14512, contrary to etoposide that kills cells DNA lesions via addition of a DNA-binding moiety deserves through targeting both isoforms. Then, we show that despite further developments. Mol Cancer Ther; 16(10); 2166–77. Ó2017 AACR. Introduction with the TOP2 poison etoposide is still a current therapy in several solid or hematologic tumors (7). Topoisomerase II (TOP2) promotes DNA decatenation or DNA Two TOP2 isoforms operate in human cells (TOP2a and supercoils relaxation through generation of transient DNA dou- TOP2b), and etoposide has been shown to target efficiently both ble-strand breaks (DSB) mediated by enzyme homodimers, (8). Since the trapping of TOP2b has been linked to site-specific which engage reversible covalent tyrosyl-phosphodiester bonds chromosomal translocations and to secondary leukemia arising (1–4). TOP2 poisons prevent religation of the DNA break by after etoposide treatment (9), research has recently focused on the targeting and stabilizing these open intermediates as enzyme– isolation of isoform-selective TOP2 poisons (5). Moreover, to drug–DNA complexes called TOP2 cleavage-complex (TOP2cc; increase selectivity toward tumor cells, new derivatives of TOP2 refs. 5, 6). TOP2 poisons, as generators of protein-linked DNA poisons have been developed. Thus, the molecule F14512 aims at breaks that effectively block transcription and replication, are exploiting the overexpression of the polyamine transport system widely used as anticancer drugs (5–7). For example, treatment (PTS) in tumors (10) through the addition to the epipodophyl- lotoxin core of a spermine moiety intended to change its cellular uptake properties (11). Indeed, in several leukemia cell lines, it was established a correlation between F14512 cytotoxicity and the 1Institut de Pharmacologie et Biologie Structurale, IPBS, Universite de Toulouse, PTS expression measured by flow cytometry with a spermine- 2 CNRS, UPS, Toulouse, France. Pierre Fabre Research Institute, CRDPF, Toulouse based fluorescent probe (12). Notably, the presence of a poly- Cedex, France. 3Equipe labellisee Ligue Nationale Contre le Cancer 2013. amine tail in F14512 has a supplementary effect, namely an Note: Supplementary data for this article are available at Molecular Cancer increased stability of the TOP2–drug–DNA complex which cor- Therapeutics Online (http://mct.aacrjournals.org/). relates with an enhanced activity of F14512 as a TOP2 poison in Current address for B. Gomes: iTeos Therapeutics, Rue Auguste Piccard 48, biochemical assays (11, 13). The stabilization of the TOP2cc by B-6041, Gosselies, Belgium. F14512 most probably depends on a combination of drug– Corresponding Author: Patrick Calsou, Institut de Pharmacologie et de Biologie protein interactions coupled to polyamine DNA interactions Structurale, 205 route de Narbonne, BP64182, F-31077 Toulouse Cedex 4, within the TOP2–drug–DNA complex (13, 14). Interestingly, France. Phone: 33-0-561175970; Fax: 33-0-561175933; E-mail: F14512 exhibited a marked increase in cytotoxic potency com- [email protected] pared with etoposide in cell proliferation assays on a large panel of doi: 10.1158/1535-7163.MCT-16-0767 human cancer cell lines (average IC50 values 8-fold lower for Ó2017 American Association for Cancer Research. F14512; refs. 11, 12) and showed also potent antitumor activity in 2166 Mol Cancer Ther; 16(10) October 2017 Downloaded from mct.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst June 13, 2017; DOI: 10.1158/1535-7163.MCT-16-0767 Polyamine Moiety in F14512 Alters TOP2cc Repair various in vivo mice models, including acute myeloid leukemia penicillin, and 100 mg/mL streptomycin. The osteosarcoma U2OS (15, 16) and in canine lymphoma (17). Therefore, a phase I study human cell line was kindly provided by Ga€elle Legube (LBCMCP, of F14512 has been completed in human hematologic patholo- University of Toulouse, Toulouse, France) in 2010 and main- gies (18), and a clinical phase II study is ongoing. tained in RPMI-1640 medium (Gibco) supplemented with 10 % At the cellular level, TOP2cc are repaired by sequential fetal calf serum and penicillin/streptomycin. The fibrosarcoma processes that are required first, for DNA ends clearing from HT1080 human cell line was kindly provided by Pierre Lutz (IPBS, the blocked TOP2 that prevents direct ligation and then, repair University of Toulouse) in 2015 and the cervical cancer HeLa cells of the remaining DSB (6, 19). Two different enzymatic pro- were initially obtained from the ATCC in 2002 and maintained in cesses can operate to remove TOP2 from the DNA ends. In the DMEM (Gibco) supplemented with 10% fetal calf serum and first one, TOP2 removal is achieved by proteasomal degrada- penicillin/streptomycin. The LIG4-defective and parental tion (20–23) followed by hydrolysis of the tyrosyl-phospho- HCT116 cell lines were a kind gift from Eric Hendrickson in diester link between a residual TOP2 peptide and DNA by the 2012 (University of Minnesota Medical School, Minneapolis, phosphodiesterase TDP2 (24), and then DNA ends in the MN) and the XLF-defective and parental HCT116 cell lines were remaining DSB are ligated by nonhomologous end-joining purchased from Horizon in 2013. HCT116 cell lines were main- (NHEJ; ref. 25). In another process, TOP2 is removed by a tained in RPMI-1640 medium supplemented with 10 % fetal calf nucleolytic attack of the DNA flanking the break ends by the serum and penicillin/streptomycin. All cells have been stored in MRE11/RAD50/NBS1 (MRN) complex together with the CtIP the laboratory as cryopreserved aliquots. After thawing, a single and BRCA1 proteins (26–31) and ATM as facilitator (32), cryovial is propagated for a maximum of 10 weeks. Cells were which is then followed by homologous recombination (HR) routinely tested for lack of mycoplasma contamination and with the intact sister chromatid (6, 19). A composite pathway grown in a humidified atmosphere, at 37 C with 5% CO2. Their mixing nucleolytic attack by MRN and ligation by NHEJ also identity was not formally verified for this study by the authors. exists in human cells (26, 33, 34). Among these various mechanisms, what is dictating the repair Compounds choice of TOP2cc in human cells is not yet clear, nor are the F14512 was provided by Institut de Recherche Pierre Fabre and consequences of this choice on cell survival. In this regard, the etoposide was purchased from Euromedex (S1225). stability of TOP2cc may be an important parameter. Biochemical assays clearly established that F14512 is a more potent stabilizer siRNA sequences and references of TOP2cc than its cognate molecule etoposide (11, 13). There- siRNA Control [CGUACGCGCCAAUACUUCGA-dTdT] and fore, we decided to compare etoposide and F14512 for the rates of siRNA CtIP [GCUAAAACAGGAACGAAUC-dTdT] were pur- TOP2cc production and resolution in human cells, for their chased from Sigma-Aldrich. susceptibility to repair by TDP2-dependent or endonucleolytic siRNA directed against TDP2 (L-017578-00-0005) and BRCA1 processes and for the susceptibility of the associated DSB to repair (L-003461-00-0010) were siRNA SMARTpool ON-TARGETplus by end-joining or resection-based processes. from Dharmacon (ThermoFisher Scientific). We report here that targeting of TOP2a and not TOP2b The siRNA TOP2a (Hs-TOP2A-6 Flexitube siRNA, SI02665068) impacts cell killing by F14512, contrary to etoposide that kills and the siRNA TOP2b (Hs-TOP2B-5 Flexitube siRNA, SI02780736) cells through targeting both isoforms. Then we show that were purchased from Qiagen. despite being more cytotoxic,
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