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Int. J. Mol. Sci. 2017, 18(7), 1435; doi:10.3390/ijms18071435

Quantitative Evaluation of Drug Resistance Profile of Cells Expressing Wild-Type or Genetic Polymorphic Variants of the Human ABC Transporter ABCC4

1
Department of Applied Biological Chemistry, Graduate School of Bioscience and Biotechnology, Chubu University, 1200 Matsumoto-cho, Kasugai 487-8501, Japan
2
Department of Applied Biological Chemistry, College of Bioscience and Biotechnology, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan
*
Author to whom correspondence should be addressed.
Received: 14 April 2017 / Revised: 30 May 2017 / Accepted: 26 June 2017 / Published: 4 July 2017
(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)
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Abstract

Broad-spectrum resistance in cancer cells is often caused by the overexpression of ABC transporters; which varies across individuals because of genetic single-nucleotide polymorphisms (SNPs). In the present study; we focused on human ABCC4 and established cells expressing the wild-type (WT) or SNP variants of human ABCC4 using the Flp-In™ system (Invitrogen, Life Technologies Corp, Carlsbad, CA, USA) based on Flp recombinase-mediated transfection to quantitatively evaluate the effects of nonsynonymous SNPs on the drug resistance profiles of cells. The mRNA levels of the cells expressing each ABCC4 variant were comparable. 3-(4,5-Dimethyl-2-thiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay clearly indicated that the EC50 values of azathioprine against cells expressing ABCC4 (WT) were 1.4–1.7-fold higher than those against cells expressing SNP variants of ABCC4 (M184K; N297S; K304N or E757K). EC50 values of 6-mercaptopurine or 7-Ethyl-10-hydroxy-camptothecin (SN-38) against cells expressing ABCC4 (WT) were also 1.4–2.0- or 1.9-fold higher than those against cells expressing the SNP variants of ABCC4 (K304N or E757K) or (K304N; P403L or E757K); respectively. These results indicate that the effects of nonsynonymous SNPs on the drug resistance profiles of cells expressing ABCC4 can be quantitatively evaluated using the Flp-In™ system. View Full-Text
Keywords: ATP-binding cassette (ABC) transporter; ATP-binding cassette subfamily C member 4 (ABCC4); drug resistance; single-nucleotide polymorphism (SNP); multi drug resistance protein 4 (MRP4) ATP-binding cassette (ABC) transporter; ATP-binding cassette subfamily C member 4 (ABCC4); drug resistance; single-nucleotide polymorphism (SNP); multi drug resistance protein 4 (MRP4)
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Tsukamoto, M.; Sato, S.; Satake, K.; Miyake, M.; Nakagawa, H. Quantitative Evaluation of Drug Resistance Profile of Cells Expressing Wild-Type or Genetic Polymorphic Variants of the Human ABC Transporter ABCC4. Int. J. Mol. Sci. 2017, 18, 1435.

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