{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:16:38Z","timestamp":1792196198525,"version":"4.4.0"},"reference-count":90,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,6]],"date-time":"2025-07-06T00:00:00Z","timestamp":1751760000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Theophrastus Paracelsus Foundation, M\u00fchltal, Germany"},{"name":"the Intramural Research Program at the National Cancer Institute (NCI) of the National Institute of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Anthracyclines have been clinically well established in cancer chemotherapy for decades. The main limitations of this drug class are the development of resistance and severe side effects. In the present investigation, we analyzed 30 anthracyclines in a panel of 59 cell lines of the National Cancer Institute, USA. The log10IC50 values varied from \u221210.49 M (3\u2032-deamino-3\u2032-(4\u2033-(3\u2033-cyano)morpholinyl)-doxorubicin, 1) to \u22124.93 M (N,N-dibenzyldaunorubicin hydrochloride, 30). Multidrug-resistant NCI-ADR-Res ovarian cancer cells revealed a high degree of resistance to established anthracyclines (between 18-fold to idarubicin (4) and 166-fold to doxorubicin (13) compared to parental, drug-sensitive OVCAR8 cells). The resistant cells displayed only low degrees of resistance (1- to 5-fold) to four other anthracyclines (7, 18, 28, 30) and were even hypersensitive (collaterally sensitive) to two compounds (1, 26). Live cell time-lapse microscopy proved the cross-resistance of the three chosen anthracyclines (4, 7, 9) on sensitive CCRF\/CEM and multidrug-resistant CEM\/ADR5000 cells. Structure\u2013activity relationships showed that the presence of tertiary amino functions is helpful in avoiding resistance, while primary amines rather increased resistance development. An \u03b1-aminonitrile function as in compound 1 was favorable. Investigating the mRNA expression of 49 ATP-binding cassette (ABC) transporter genes showed that ABCB1\/MDR1 encoding P-glycoprotein was the most important one for acquired and inherent resistance to anthracyclines. Molecular docking demonstrated that all anthracyclines bound to the same binding domain at the inner efflux channel side of P-glycoprotein with high binding affinities. Kaplan\u2013Meier statistics of RNA sequencing data of more than 8000 tumor biopsies of TCGA database revealed that out of 23 tumor entities high ABCB1 expression was significantly correlated with worse survival times for acute myeloid leukemia, multiple myeloma, and hepatocellular carcinoma patients. This indicates that ABCB1 may serve as a prognostic marker in anthracycline-based chemotherapy regimens in these tumor types and a target for the development of novel anthracycline derivatives.<\/jats:p>","DOI":"10.3390\/biom15070971","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T11:19:27Z","timestamp":1751887167000},"page":"971","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Predictive and Prognostic Relevance of ABC Transporters for Resistance to Anthracycline Derivatives"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9678-3323","authenticated-orcid":false,"given":"R\u00fcmeysa","family":"Y\u00fccer","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossana","family":"Piccinno","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology, Ackermannweg 4, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8275-927X","authenticated-orcid":false,"given":"Ednah","family":"Ooko","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"Department of Biological Sciences, School of Natural and Applied Sciences, Masinde Muliro University of Science and Technology, Kakamega 190-50100, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona","family":"Dawood","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany"},{"name":"Department of Molecular Biology, Faculty of Medical Laboratory Sciences, Al-Neelain University, Khartoum 12702, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3583-5935","authenticated-orcid":false,"given":"Gerhard","family":"Bringmann","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry, University of W\u00fcrzburg, Am Hubland, 97074 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2637-1681","authenticated-orcid":false,"given":"Thomas","family":"Efferth","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,6]]},"reference":[{"key":"ref_1","first-page":"138","article-title":"Relevance of In Vitro tests for predicting responsiveness to antitumor agents","volume":"34","author":"Kessel","year":"1971","journal-title":"Natl. 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