title: The RAD51-stimulatory compound RS-1 can exploit the RAD51 overexpression that exists in cancer cells and tumors.
abstract: RAD51 is the central protein that catalyzes DNA repair via homologous recombination, a process that ensures genomic stability. RAD51 protein is commonly expressed at high levels in cancer cells relative to their noncancerous precursors. High levels of RAD51 expression can lead to the formation of genotoxic RAD51 protein complexes on undamaged chromatin. We developed a therapeutic approach that exploits this potentially toxic feature of malignancy, using compounds that stimulate the DNA-binding activity of RAD51 to promote cancer cell death. A panel of immortalized cell lines was challenged with the RAD51-stimulatory compound RS-1. Resistance to RS-1 tended to occur in cells with higher levels of RAD54L and RAD54B, which are Swi2/Snf2-related translocases known to dissociate RAD51 filaments from dsDNA. In PC3 prostate cancer cells, RS-1-induced lethality was accompanied by the formation of microscopically visible RAD51 nuclear protein foci occurring in the absence of any DNA-damaging treatment. Treatment with RS-1 promoted significant antitumor responses in a mouse model, providing proof-of-principle for this novel therapeutic strategy.
authors.affiliation: Authors' Affiliations: Department of Radiation and Cellular Oncology.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Mason
authors.affiliation: Authors' Affiliations: Department of Radiation and Cellular Oncology.
authors.forename: Hillary L
authors.initials: HL
authors.lastname: Logan
authors.affiliation: Authors' Affiliations: Department of Radiation and Cellular Oncology.
authors.forename: Brian
authors.initials: B
authors.lastname: Budke
authors.affiliation: Authors' Affiliations: Department of Radiation and Cellular Oncology.
authors.forename: Megan
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Drug Discovery Program, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Michal
authors.initials: M
authors.lastname: Pawlowski
authors.affiliation: Authors' Affiliations: Department of Radiation and Cellular Oncology, Ludwig Center for Metastasis Research.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Drug Discovery Program, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.affiliation: Authors' Affiliations: Department of Radiation and Cellular Oncology, Department of Molecular Genetics and Cell Biology, University of Chicago; and.
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Bishop
authors.affiliation: Authors' Affiliations: Department of Radiation and Cellular Oncology, pconnell@radonc.uchicago.edu.
authors.forename: Philip P
authors.initials: PP
authors.lastname: Connell
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism; D004265:DNA Helicases / Q000096:biosynthesis / Q000235:genetics*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins; D057809:HEK293 Cells; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D011485:Protein Binding; D034622:RNA Interference; D051135:Rad51 Recombinase / Q000096:biosynthesis / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C000592317:3-(N-benzylsulfamoyl)-4-bromo-N-(4-bromophenyl)benzamide; D001549:Benzamides; D002843:Chromatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D013449:Sulfonamides; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse; D004265:DNA Helicases; C103534:Rad54l protein, mouse; C552322:rad54b protein, mouse
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