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Interaction of the P-glycoprotein multidrug transporter (MDR1) with high affinity peptide chemosensitizers in isolated membranes, reconstituted systems, and intact cells.
Sharom, F J; Yu, X; Lu, P; Liu, R; Chu, J W; Szabó, K; Müller, M; Hose, C D; Monks, A; Váradi, A; Seprôdi, J; Sarkadi, B.
Afiliação
  • Sharom FJ; Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, Department of Chemistry and Biochemistry, University of Guelph, Ontario, Canada. sharom@chembio.uoguelph.ca
Biochem Pharmacol ; 58(4): 571-86, 1999 Aug 15.
Article em En | MEDLINE | ID: mdl-10413294
ABSTRACT
P-glycoprotein-mediated multidrug resistance can be reversed by the action of a group of compounds known as chemosensitizers. The interactions with P-glycoprotein of two novel hydrophobic peptide chemosensitizers (reversins 121 and 205) have been studied in model systems in vitro, and in a variety of MDR1-expressing intact tumor cells. The reversins bound to purified P-glycoprotein with high affinity (77-154 nM), as assessed by a quenching assay using fluorescently labeled purified protein. The peptides modulated P-glycoprotein ATPase activity in Sf9 insect cell membranes expressing human MDR1, plasma membrane vesicles from multidrug-resistant cells, and reconstituted proteoliposomes. Both peptides induced a large stimulation of ATPase activity; however, higher concentrations, especially of reversin 205, led to inhibition. This pattern was different from that of simple linear peptides, and resembled that of chemosensitizers such as verapamil. In both membrane vesicles and reconstituted proteoliposomes, 1-2 microM reversins were more effective than cyclosporin A at blocking colchicine transport. Reversin 121 and reversin 205 restored the uptake of [3H]daunorubicin and rhodamine 123 in MDR1-expressing cells to the level observed in the drug-sensitive parent cell lines, and also effectively inhibited the extrusion of calcein acetoxymethyl ester from intact cells. In cytotoxicity assays, reversin 121 and reversin 205 eliminated the resistance of MDR1-expressing tumor cells against MDR1-substrate anticancer drugs, and they had no toxic effects in MDR1-negative control cells. We suggest that peptides of the reversin type interact with the MDR1 protein with high affinity and specificity, and thus they may be good candidates for the development of MDR1-modulating agents to sensitize drug resistance in cancer.
Assuntos
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Coleções: 01-internacional Contexto em Saúde: 6_ODS3_enfermedades_notrasmisibles Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Peptídeos / Membrana Celular / Membro 1 da Subfamília B de Cassetes de Ligação de ATP / Resistência a Múltiplos Medicamentos / Resistencia a Medicamentos Antineoplásicos Limite: Animals / Humans Idioma: En Revista: Biochem Pharmacol Ano de publicação: 1999 Tipo de documento: Article
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Coleções: 01-internacional Contexto em Saúde: 6_ODS3_enfermedades_notrasmisibles Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Peptídeos / Membrana Celular / Membro 1 da Subfamília B de Cassetes de Ligação de ATP / Resistência a Múltiplos Medicamentos / Resistencia a Medicamentos Antineoplásicos Limite: Animals / Humans Idioma: En Revista: Biochem Pharmacol Ano de publicação: 1999 Tipo de documento: Article