Comparative In Vitro Study of the Cytotoxic Effects of Doxorubicin's Main Metabolites on Cardiac AC16 Cells Versus the Parent Drug

• Type: Article in International Scientific Journal
• Date: 2024

Authors

Reis-Mendes, A (Author) Other; Vitorino-Oliveira, C (Author) Other; Ferreira, M (Author) Other; Felix Carvalho (Author) FFUP; Fernando Remiao (Author) FFUP; Emilia Sousa (Author) FFUP; Bastos, MD (Author) Other; Costa, VM (Author) Other

Journal

Title: Cardiovascular Toxicology

Vol. 24

Pages: 266-279

ISSN: 1530-7905

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 0 Citations

Scopus

Other information

Authenticus ID: P-010-02T

DOI: 10.1007/s12012-024-09829-6

Abstract (EN): 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 mu M, while diallyl sulphide (a CYP2E1 inhibitor) decreased the 1 mu M DOX-triggered cytotoxicity. Then, the toxicity of the main DOX metabolites, doxorubicinol [(DOXol, 0.5 to 10 mu M), doxorubicinone (DOXone, 1 to 10 mu M), and 7-deoxydoxorubicinone (7-DeoxyDOX, 1 to 10 mu M)] was compared to DOX (0.5 to 10 mu M) following a 48-h exposure. All metabolites evaluated, DOXol, DOXone, and 7-DeoxyDOX caused mitochondrial dysfunction in differentiated AC16 cells, but only at 2 mu M. 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14