The effects of anthracycline drugs on the conformational distribution of mouse P-glycoprotein explains their transport rate differences.
Biochem Pharmacol
; 174: 113813, 2020 04.
Article
em En
| MEDLINE
| ID: mdl-31954717
ABSTRACT
P-glycoprotein (Pgp) is an ATP-dependent efflux transporter and plays a major role in anti-cancer drug resistance by pumping a chemically diverse range of cytotoxic drugs from cancerous tumors. Despite numerous studies with the transporter, the molecular features that drive anti-cancer drug efflux are not well understood. Even subtle differences in the anti-cancer drug molecular structure can lead to dramatic differences in their transport rates. To unmask these structural differences, this study focused on two closely-related anthracycline drugs, daunorubicin (DNR), and doxorubicin (DOX), with mouse Pgp. While only differing by a single hydroxyl functional group, DNR has a 4 to 5-fold higher transport rate than DOX. They both non-competitively inhibited Pgp-mediated ATP hydrolysis below basal levels. The Km of Pgp-mediated ATP hydrolysis extracted from the kinetics curves was lower for DOX than DNR. However, the dissociation constants (KDs) for these drugs determined by fluorescence quenching were virtually identical. Acrylamide quenching of Pgp tryptophan fluorescence to probe the tertiary structure of Pgp suggested that DNR shifts Pgp to a "closed" conformation, while DOX shifts Pgp to an "intermediate" conformation. The effects of these drugs on the Pgp conformational distributions in a lipid bilayer were also examined by atomic force microscopy (AFM). Analysis of AFM images revealed that DNR and DOX cause distinct and significant shifts in the conformational distribution of Pgp. The results were combined to build a conformational distribution model for anthracycline transport by Pgp.
Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Daunorrubicina
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Doxorrubicina
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP
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Antraciclinas
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Antibióticos Antineoplásicos
Limite:
Animals
Idioma:
En
Revista:
Biochem Pharmacol
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos