{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T15:35:16Z","timestamp":1773243316514,"version":"3.50.1"},"reference-count":56,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,1,10]],"date-time":"2019-01-10T00:00:00Z","timestamp":1547078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o da Ci\u00eancia e da Tecnologia","award":["PTDC\/DTP-FTO\/1489\/2014 \u2013 POCI-01-0145-FEDER-016537"],"award-info":[{"award-number":["PTDC\/DTP-FTO\/1489\/2014 \u2013 POCI-01-0145-FEDER-016537"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Currently, a common therapeutic approach in cancer treatment encompasses a drug combination to attain an overall better efficacy. Unfortunately, it leads to a higher incidence of severe side effects, namely cardiotoxicity. This work aimed to assess the cytotoxicity of doxorubicin (DOX, also known as Adriamycin), 5-fluorouracil (5-FU), cyclophosphamide (CYA), and their combination (5-Fluorouracil + Adriamycin + Cyclophosphamide, FAC) in H9c2 cardiac cells, for a better understanding of the contribution of each drug to FAC-induced cardiotoxicity. Differentiated H9c2 cells were exposed to pharmacological relevant concentrations of DOX (0.13\u20135 \u03bcM), 5-FU (0.13\u20135 \u03bcM), CYA (0.13\u20135 \u03bcM) for 24 or 48 h. Cells were also exposed to FAC mixtures (0.2, 1 or 5 \u03bcM of each drug and 50 \u03bcM 5-FU + 1 \u03bcM DOX + 50 \u03bcM CYA). DOX was the most cytotoxic drug, followed by 5-FU and lastly CYA in both cytotoxicity assays (reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and neutral red (NR) uptake). Concerning the equimolar combination with 1 or 5 \u03bcM, FAC caused similar cytotoxicity to DOX alone. Even in the presence of higher concentrations of 5-FU and CYA (50 \u03bcM 5-FU + 1 \u03bcM DOX + 50 \u03bcM CYA), 1 \u03bcM DOX was still a determinant for the cardiotoxicity observed in the cytotoxicity assays, phase contrast morphological evaluation, and mitochondrial potential depolarization evaluation. To the best of our knowledge, this was the first in vitro work with this combination regimen, DOX being the most toxic drug and key to the toxicity of FAC.<\/jats:p>","DOI":"10.3390\/biom9010021","type":"journal-article","created":{"date-parts":[[2019,1,11]],"date-time":"2019-01-11T04:10:16Z","timestamp":1547179816000},"page":"21","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Doxorubicin Is Key for the Cardiotoxicity of FAC (5-Fluorouracil + Adriamycin + Cyclophosphamide) Combination in Differentiated H9c2 Cells"],"prefix":"10.3390","volume":"9","author":[{"given":"Maria","family":"Pereira-Oliveira","sequence":"first","affiliation":[{"name":"UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2775-3147","authenticated-orcid":false,"given":"Ana","family":"Reis-Mendes","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]},{"given":"F\u00e9lix","family":"Carvalho","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-5119","authenticated-orcid":false,"given":"Fernando","family":"Remi\u00e3o","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]},{"given":"Maria de Lourdes","family":"Bastos","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0471-2756","authenticated-orcid":false,"given":"Vera Marisa","family":"Costa","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2019,1,10]]},"reference":[{"key":"ref_1","unstructured":"Kufe, D.W., Pollock, R.E., Bast, R.C., and Weichselbaum, R.R. 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