title: A ROS-Activatable Agent Elicits Homologous Recombination DNA Repair and Synergizes with Pathway Compounds.
abstract: We designed ROS-activated cytotoxic agents (RACs) that are active against AML cancer cells. In this study, the mechanism of action and synergistic effects against cells coexpressing the AML oncogenes MLL-AF9 fusion and FLT3-ITD were investigated. One RAC (RAC1) had an IC50 value of 1.8±0.3 μm, with ninefold greater selectivity for transformed cells compared to untransformed cells. Treatment induced DNA strand breaks, apoptosis, and cell cycle arrest. Proteomics and transcriptomics revealed enhanced expression of the pentose phosphate pathway, DNA repair, and pathways common to cell stress. Western blotting confirmed repair by homologous recombination. Importantly, RAC1 treatment was synergistic in combination with multiple pathway-targeting therapies in AML cells but less so in untransformed cells. Together, these results demonstrate that RAC1 can selectively target poor prognosis AML and that it does so by creating DNA double-strand breaks that require homologous recombination.
authors.affiliation: Department of Chemistry, University of Cincinnati, 404 Crosley Tower, Cincinnati, OH, 45221-0172, USA.
authors.forename: Fathima Shazna
authors.initials: FS
authors.lastname: Thowfeik
authors.affiliation: Department of Chemistry, University of Cincinnati, 404 Crosley Tower, Cincinnati, OH, 45221-0172, USA.
authors.forename: Safnas F
authors.initials: SF
authors.lastname: AbdulSalam
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45221, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45221, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wyder
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45221, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Greis
authors.affiliation: Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, OH, 45221, USA.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Kadekaro
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45221, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.affiliation: Department of Chemistry, University of Cincinnati, 404 Crosley Tower, Cincinnati, OH, 45221-0172, USA. merinoed@ucmail.uc.edu.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Merino
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D019800:Phenol / Q000737:chemistry* / Q000633:toxicity; D040901:Proteomics; D017382:Reactive Oxygen Species / Q000378:metabolism; D059767:Recombinational DNA Repair / Q000187:drug effects*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009687:Nuclear Proteins; C000611438:RAC1 compound; D017382:Reactive Oxygen Species; D019800:Phenol; D004247:DNA
keywords: ROS; acute myeloid leukemia; cytotoxicity; homologous recombination; mechanism of action