Human ATP-binding cassette transporters ABCB1 and ABCG2 confer resistance to histone deacetylase 6 inhibitor ricolinostat (ACY-1215) in cancer cell lines.
Biochem Pharmacol
; 155: 316-325, 2018 09.
Article
em En
| MEDLINE
| ID: mdl-30028995
ABSTRACT
Ricolinostat is the first orally available, selective inhibitor of histone deacetylase 6 (HDAC6), currently under evaluation in clinical trials in patients with various malignancies. It is likely that the inevitable emergence of resistance to ricolinostat is likely to reduce its clinical effectiveness in cancer patients. In this study, we investigated the potential impact of multidrug resistance-linked ATP-binding cassette (ABC) transporters ABCB1 and ABCG2 on the efficacy of ricolinostat, which may present a major hurdle to its development as an anticancer drug in the future. We demonstrated that the overexpression of ABCB1 or ABCG2 reduces the intracellular accumulation of ricolinostat, resulting in reduced efficacy of ricolinostat to inhibit the activity of HDAC6 in cancer cells. Moreover, the efficacy of ricolinostat can be fully restored by inhibiting the drug efflux function of ABCB1 and ABCG2 in drug-resistant cancer cells. In conclusion, our results provide some insights into the basis for the development of resistance to ricolinostat and suggest that co-administration of ricolinostat with a modulator of ABCB1 or ABCG2 could overcome ricolinostat resistance in human cancer cells, which may be relevant to its use in the clinic.
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Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
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Resistencia a Medicamentos Antineoplásicos
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Inibidores de Histona Desacetilases
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Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP
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Desacetilase 6 de Histona
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Ácidos Hidroxâmicos
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Proteínas de Neoplasias
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article