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Comparative In Vitro Study of the Cytotoxic Effects of Doxorubicin's Main Metabolites on Cardiac AC16 Cells Versus the Parent Drug.
Reis-Mendes, Ana; Vitorino-Oliveira, Cláudia; Ferreira, Mariana; Carvalho, Félix; Remião, Fernando; Sousa, Emília; de Lourdes Bastos, Maria; Costa, Vera Marisa.
Afiliación
  • Reis-Mendes A; Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
  • Vitorino-Oliveira C; Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, UCIBIO - Applied Molecular Biosciences Unit, University of Porto, 4050-313, Porto, Portugal.
  • Ferreira M; Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
  • Carvalho F; Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, UCIBIO - Applied Molecular Biosciences Unit, University of Porto, 4050-313, Porto, Portugal.
  • Remião F; Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
  • Sousa E; Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, UCIBIO - Applied Molecular Biosciences Unit, University of Porto, 4050-313, Porto, Portugal.
  • de Lourdes Bastos M; Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
  • Costa VM; Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, UCIBIO - Applied Molecular Biosciences Unit, University of Porto, 4050-313, Porto, Portugal.
Cardiovasc Toxicol ; 24(3): 266-279, 2024 Mar.
Article en En | MEDLINE | ID: mdl-38347287
ABSTRACT
Doxorubicin (DOX; also known as adriamycin) serves as a crucial antineoplastic agent in cancer treatment; however, its clinical utility is hampered by its' intrinsic cardiotoxicity. Although most DOX biotransformation occurs in the liver, a comprehensive understanding of the impact of DOX biotransformation and its' metabolites on its induced cardiotoxicity remains to be fully elucidated. This study aimed to explore the role of biotransformation and DOX's main metabolites in its induced cardiotoxicity in human differentiated cardiac AC16 cells. A key discovery from our study is that modulating metabolism had minimal effects on DOX-induced cytotoxicity even so, metyrapone (a non-specific inhibitor of cytochrome P450) increased DOX-induced cytotoxicity at 2 µM, while diallyl sulphide (a CYP2E1 inhibitor) decreased the 1 µM DOX-triggered cytotoxicity. Then, the toxicity of the main DOX metabolites, doxorubicinol [(DOXol, 0.5 to 10 µM), doxorubicinone (DOXone, 1 to 10 µM), and 7-deoxydoxorubicinone (7-DeoxyDOX, 1 to 10 µM)] was compared to DOX (0.5 to 10 µM) following a 48-h exposure. All metabolites evaluated, DOXol, DOXone, and 7-DeoxyDOX caused mitochondrial dysfunction in differentiated AC16 cells, but only at 2 µM. In contrast, DOX elicited comparable cytotoxicity, but at half the concentration. Similarly, all metabolites, except 7-DeoxyDOX impacted on lysosomal ability to uptake neutral red. Therefore, the present study showed that the modulation of DOX metabolism demonstrated minimal impact on its cytotoxicity, with the main metabolites exhibiting lower toxicity to AC16 cardiac cells compared to DOX. In conclusion, our findings suggest that metabolism may not be a pivotal factor in mediating DOX's cardiotoxic effects.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cardiotoxicidad / Antineoplásicos Límite: Humans Idioma: En Revista: Cardiovasc Toxicol Asunto de la revista: ANGIOLOGIA / CARDIOLOGIA / TOXICOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Portugal Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cardiotoxicidad / Antineoplásicos Límite: Humans Idioma: En Revista: Cardiovasc Toxicol Asunto de la revista: ANGIOLOGIA / CARDIOLOGIA / TOXICOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Portugal Pais de publicación: Estados Unidos