Naphthoquinoxaline metabolite of mitoxantrone is less cardiotoxic than the parent compound and it can be a more cardiosafe drug in anticancer therapy

• Type: Article in International Scientific Journal
• Date: 2017

Authors

Reis Mendes, A (Author) Other; Gomes, AS (Author) Other; Carvalho, RA (Author) Other; Felix Carvalho (Author) FFUP; Fernando Remiao (Author) FFUP; Pinto, M (Author) Other; Maria de Lourdes Bastos (Author) FFUP; Emilia Sousa (Author) FFUP; Costa, VM (Author) Other

Journal

Title: Archives of Toxicology

Vol. 91

Pages: 1871-1890

ISSN: 0340-5761

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 13 Citations

Scopus - 16 Citations

Other information

Authenticus ID: P-00K-VD8

DOI: 10.1007/s00204-016-1839-z

Abstract (EN): Mitoxantrone (MTX) is an antineoplastic agent used to treat several types of cancers and on multiple sclerosis, which shows a high incidence of cardiotoxicity. Still, the underlying mechanisms of MTX cardiotoxicity are poorly understood and the potential toxicity of its metabolites scarcely investigated. Therefore, this work aimed to synthesize the MTX-naphthoquinoxaline metabolite (NAPHT) and to compare its cytotoxicity to the parent compound in 7-day differentiated H9c2 cells using pharmacological relevant concentrations (0.01-5 A mu M). MTX was more toxic in equivalent concentrations in all cytotoxicity tests performed [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction, neutral red uptake, and lactate dehydrogenase release assays] and times tested (24 and 48 h). Both MTX and NAPHT significantly decreased mitochondrial membrane potential in 7-day differentiated H9c2 cells after a 12-h incubation. However, energetic pathways were affected in a different manner after MTX or NAPHT incubation. ATP increased and lactate levels decreased after a 24-h incubation with MTX, whereas for the same incubation time and concentrations, NAPHT did not cause any significant effect. The increased activity of ATP synthase seems responsible for MTX-induced increases in ATP levels, as oligomycin (an inhibitor of ATP synthase) abrogated this effect on 5 A mu M MTX-incubated cells. 3-Methyladenine (an autophagy inhibitor) was the only molecule to give a partial protection against the cytotoxicity produced by MTX or NAPHT. To the best of our knowledge, this was the first broad study on NAPHT cardiotoxicity, and it revealed that the parent drug, MTX, caused a higher disruption in the energetic pathways in a cardiac model in vitro, whereas autophagy is involved in the toxicity of both compounds. In conclusion, NAPHT is claimed to largely contribute to MTX-anticancer properties; therefore, this metabolite should be regarded as a good option for a safer anticancer therapy since it is less cardiotoxic than MTX.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 20