Repurposing cephalosporin antibiotics as pro-senescent radiosensitizers
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Edwardine Labay1,*, Helena J. Mauceri1,*, Elena V. Efimova2,*, Amy C. Flor2, Harold G. Sutton1, Stephen J. Kron2,3 and Ralph R. Weichselbaum1,3
1 Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA
2 Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL, USA
3 Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA
* These authors have contributed equally to this work
Ralph R. Weichselbaum, email:
Keywords: radiosensitizer, cephalosporin, drug repurposing, senescence, reactive oxygen species
Received: April 07, 2016 Accepted: April 13, 2016 Published: April 25, 2016
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.
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