title: Identification of a putative Tdp1 inhibitor (CD00509) by in vitro and cell-based assays.
abstract: Mutations of DNA repair pathways contribute to tumorigenesis and provide a therapeutic target for synthetic lethal interactions in tumor cells. Given that tyrosyl-DNA phosphodiesterase 1 (Tdp1) repairs stalled topoisomerase-I DNA complexes, we hypothesized that inhibition of Tdp1 has synthetic lethal effects in some cancers. To test this, we screened tumor arrays for Tdp1 expression and observed that Tdp1 is expressed in many tumors, including more than 90% of human breast tumors. Subsequent chemical screening identified putative Tdp1 inhibitors. Treatment of control human mammary epithelial cells and the breast cancer cell line MCF-7 with compound CD00509 preferentially sensitized MCF-7 cells to camptothecin and decreased cell proliferation 25% more than camptothecin treatment alone. This suggests that CD00509 specifically targeted Tdp1 in vitro, and CD00509 increased the sensitivity of wild-type murine embryonic fibroblasts (MEFs) to camptothecin to a degree comparable to that of Tdp1(-/-) MEFs. In addition, consistent with poly ADP-ribose polymerase-1 (PARP-1) collaborating with Tdp1 in DNA repair, combined Tdp1 and PARP-1 inhibition was more detrimental to MCF-7 cells than either treatment alone, whereas the combination was not additively harmful to control mammary cells. We conclude that targeting Tdp1 in anticancer therapy preferentially enhances the sensitivity of some breast cancer cells to camptothecin and may be an effective adjuvant for breast cancer therapy.
authors.affiliation: Centre for Drug Research and Development, Vancouver, BC, Canada.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Dean
authors.affiliation: Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Hok Khim
authors.initials: HK
authors.lastname: Fam
authors.affiliation: Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Jianghong
authors.initials: J
authors.lastname: An
authors.affiliation: Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Kunho
authors.initials: K
authors.lastname: Choi
authors.affiliation: Centre for Drug Research and Development, Vancouver, BC, Canada.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Steven J M
authors.initials: SJ
authors.lastname: Jones
authors.affiliation: Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Boerkoel
authors.affiliation: Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Interthal
authors.affiliation: Centre for Drug Research and Development, Vancouver, BC, Canada tpfeifer@cdrd.ca.
authors.forename: Tom A
authors.initials: TA
authors.lastname: Pfeifer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D057166:High-Throughput Screening Assays / Q000379:methods*; D006657:Histones / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D061986:MCF-7 Cells / Q000187:drug effects; D051379:Mice; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011714:Pyrans / Q000494:pharmacology*; D013858:Thiobarbiturates / Q000494:pharmacology*; D046888:Tissue Array Analysis; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C000602322:CD00509; C468783:H2AX protein, human; D006657:Histones; D010726:Phosphodiesterase Inhibitors; D011714:Pyrans; D013858:Thiobarbiturates; D059004:Topoisomerase I Inhibitors; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human; C524959:Tdp1 protein, mouse
keywords: cancer and cancer drugs; cell-based assays; compound repositories; high content screening