title: Novel irreversible small molecule inhibitors of replication protein A display single-agent activity and synergize with cisplatin.
abstract: Replication protein A (RPA) is a single-strand DNA-binding protein with essential roles in DNA replication, recombination, and repair. It is necessary for the formation of the preincision complex that is required for proper incision of damaged DNA nucleotides during DNA repair. We have previously identified small molecule inhibitors (SMI) with the ability to disrupt RPA-binding activity to ssDNA. Further characterization of these RPA inhibitors was done using both lung and ovarian cancer cell lines. Lung cancer cell lines showed increased apoptotic cell death following treatment with the SMI MCI13E, with IC(50) values of approximately 5 μmol/L. The ovarian cancer cell line A2780 and the p53-null lung cancer cell line H1299 were particularly sensitive to MCI13E treatment, with IC(50) values less than 3 μmol/L. Furthermore, a cell-cycle effect was observed in lung cancer cell lines that resulted in a lengthening of either G(1) or S-phases of the cell cycle following single-agent treatment. Sequential treatment with MCI13E and cisplatin resulted in synergism. Overall, these data suggest that decreasing DNA-binding activity of RPA via a SMI may disrupt the role of RPA in cell-cycle regulation. Thus, SMIs of RPA hold the potential to be used as single-agent chemotherapeutics or in combination with current chemotherapeutic regimens to increase efficacy.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Neher
authors.forename: Diane
authors.initials: D
authors.lastname: Bodenmiller
authors.forename: Richard W
authors.initials: RW
authors.lastname: Fitch
authors.forename: Shadia I
authors.initials: SI
authors.lastname: Jalal
authors.forename: John J
authors.initials: JJ
authors.lastname: Turchi
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001892:Camphanes / Q000737:chemistry* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D004277:DNA, Single-Stranded / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051716:Replication Protein A / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries
chemical_list: D001892:Camphanes; D004273:DNA, Neoplasm; D004277:DNA, Single-Stranded; D051716:Replication Protein A; D054852:Small Molecule Libraries; C022871:isoborneol; D002945:Cisplatin