{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:48:20Z","timestamp":1791388100245,"version":"4.3.3"},"reference-count":35,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,3,10]],"date-time":"2020-03-10T00:00:00Z","timestamp":1583798400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:p>\n                    Platinum\u2010based compounds remain a well\u2010established chemotherapy for cancer treatment despite their adverse effects which substantially restrict the therapeutic windows of the drugs. Both the cell type\u2010specific toxicity and the clinical responsiveness of tumors have been associated with mechanisms that alter drug entry and export. We sought to identify pharmacological agents that promote cisplatin (CP) efficacy by augmenting the levels of drug\u2010induced DNA lesions in malignant cells and simultaneously protecting normal tissues from accumulating such damage and from functional loss. Formation and persistence of platination products in the DNA of individual nuclei were measured in drug\u2010exposed cell lines, in primary human tumor cells and in tissue sections using an immunocytochemical method. Using a mouse model of CP\u2010induced toxicity, the antihistaminic drug diphenhydramine (DIPH) and two methylated derivatives decreased DNA platination in normal tissues and also ameliorated nephrotoxicity, ototoxicity, and neurotoxicity. In addition, DIPH sensitized multiple cancer cell types, particularly ovarian cancer\u00a0cells, to CP by increasing intracellular uptake, DNA platination, and\/or apoptosis in cell lines and in patient\u2010derived primary tumor cells. Mechanistically, DIPH diminished transport capacity of CP efflux pumps MRP2, MRP3, and MRP5 particularly in its C2+C6 bimethylated form. Overall, we demonstrate that DIPH reduces side effects of platinum\u2010based chemotherapy and simultaneously inhibits key mechanisms of platinum resistance. We propose that measuring DNA platination after\n                    <jats:italic>ex\u00a0vivo<\/jats:italic>\n                    exposure may predict the responsiveness of individual tumors to DIPH\u2010like modulators.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.12648","type":"journal-article","created":{"date-parts":[[2020,2,10]],"date-time":"2020-02-10T00:11:48Z","timestamp":1581293508000},"page":"686-703","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Diphenhydramine increases the therapeutic window for platinum drugs by simultaneously sensitizing tumor cells and protecting normal cells"],"prefix":"10.1002","volume":"14","author":[{"given":"Margarita","family":"Melnikova","sequence":"first","affiliation":[{"name":"Institute of Cell Biology (Cancer Research) University of Duisburg\u2010Essen Medical School Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike 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Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Dresden, Germany; Helmholtz\u2010Zentrum Dresden \u2010 Rossendorf (HZDR) Dresden Germany"},{"name":"German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ) Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3820-3017","authenticated-orcid":false,"given":"Jan Dominik","family":"Kuhlmann","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics Medical Faculty and University Hospital Carl Gustav Carus Technische Universit\u00e4t Dresden Germany"},{"name":"National Center for Tumor Diseases (NCT), Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden, Dresden, Germany; Helmholtz\u2010Zentrum Dresden 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