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Biomolecules 2019, 9(1), 21; https://doi.org/10.3390/biom9010021

Doxorubicin Is Key for the Cardiotoxicity of FAC (5-Fluorouracil + Adriamycin + Cyclophosphamide) Combination in Differentiated H9c2 Cells

UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
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Received: 4 October 2018 / Revised: 28 December 2018 / Accepted: 3 January 2019 / Published: 10 January 2019
(This article belongs to the Special Issue Multidrug Combinations)
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Abstract

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 (0.13–5 μM), 5-FU (0.13–5 μM), CYA (0.13–5 μM) for 24 or 48 h. Cells were also exposed to FAC mixtures (0.2, 1 or 5 μM of each drug and 50 μM 5-FU + 1 μM DOX + 50 μM 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 μM, FAC caused similar cytotoxicity to DOX alone. Even in the presence of higher concentrations of 5-FU and CYA (50 μM 5-FU + 1 μM DOX + 50 μM CYA), 1 μM 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. View Full-Text
Keywords: doxorubicin; 5-fluorouracil; cyclophosphamide; cardiotoxicity; differentiated H9c2 cells; FAC doxorubicin; 5-fluorouracil; cyclophosphamide; cardiotoxicity; differentiated H9c2 cells; FAC
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Pereira-Oliveira, M.; Reis-Mendes, A.; Carvalho, F.; Remião, F.; Bastos, M.L.; Costa, V.M. Doxorubicin Is Key for the Cardiotoxicity of FAC (5-Fluorouracil + Adriamycin + Cyclophosphamide) Combination in Differentiated H9c2 Cells. Biomolecules 2019, 9, 21.

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