title: Repurposing cephalosporin antibiotics as pro-senescent radiosensitizers.
abstract: Radiation therapy remains a significant therapeutic modality in the treatment of cancer. An attractive strategy would be to enhance the benefits of ionizing radiation (IR)with radiosensitizers. A high-content drug repurposing screen of approved and investigational agents, natural products and other small molecules has identified multiple candidates that blocked repair of IR damage in vitro. Here, we validated a subset of these hits in vitro and then examined effects on tumor growth after IR in a murine tumor model. Based on robust radiosensitization in vivo and other favorable properties of cephalexin, we conducted additional studies with other beta-lactam antibiotics. When combined with IR, each cephalosporin tested increased DNA damage and slowed tumor growth without affecting normal tissue toxicity. Our data implicate reactive oxygen species in the mechanism by which cephalosporins augment the effects of IR. This work provides a rationale for using commonly prescribed beta-lactam antibiotics as non-toxic radiosensitizers to enhance the therapeutic ratio of radiotherapy.
authors.affiliation: Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA.
authors.forename: Edwardine
authors.initials: E
authors.lastname: Labay
authors.affiliation: Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA.
authors.forename: Helena J
authors.initials: HJ
authors.lastname: Mauceri
authors.affiliation: Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL, USA.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Efimova
authors.affiliation: Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Flor
authors.affiliation: Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA.
authors.forename: Harold G
authors.initials: HG
authors.lastname: Sutton
authors.affiliation: Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL, USA.|Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kron
authors.affiliation: Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA.|Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D049109:Cell Proliferation / Q000187:drug effects* / Q000528:radiation effects*; D016922:Cellular Senescence / Q000187:drug effects* / Q000528:radiation effects*; D002511:Cephalosporins / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D058492:Drug Repositioning; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species
keywords: cephalosporin; drug repurposing; radiosensitizer; reactive oxygen species; senescence