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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 4/2016

01-10-2016 | Original Article

Discovery of LW6 as a new potent inhibitor of breast cancer resistance protein

Authors: Jae Guen Song, Yeo Song Lee, Jin-Ah Park, Eun-Hye Lee, Soo-Jeong Lim, Seung Jun Yang, Mengjia Zhao, Kyeong Lee, Hyo-Kyung Han

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2016

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Abstract

Purpose

The present study aimed to discover a new potent BCRP inhibitor overcoming multidrug resistance.

Methods

Effects of LW6 on the functional activity and gene expression of two major efflux transporters, BCRP and P-gp, were evaluated by using MDCKII cells overexpressing each transporter (MDCKII-BCRP and MDCKII-MDR1). Its effects on the cytotoxicity and pharmacokinetics of co-administered anticancer drugs were also evaluated in transfected cells and rats, respectively.

Results

In MDCKII-BCRP cells overexpressing BCRP, LW6 enhanced significantly (p < 0.05) the cellular accumulation of mitoxantrone, a BCRP substrate, and was more potent than Ko143, a well-known BCRP inhibitor. LW6 also down-regulated BCRP expression at concentrations of 0.1–10 µM. Furthermore, cells became more susceptible to the cytotoxicity of anticancer drugs in the presence of LW6. The CC50 values of mitoxantrone and doxorubicin were reduced by three- and tenfold, respectively, in MDCKII-BCRP cells, while LW6 did not affect the cytotoxicity of anticancer drugs in MDCKII-mock cells lacking BCRP transporter. Furthermore, LW6 improved the oral exposure of methotrexate by twofold in rats. In contrast to BCRP, LW6 had no inhibition effect on the functional activity and gene expression of P-gp.

Conclusion

LW6 was newly identified as a potent BCRP inhibitor and could be useful to reduce the multidrug resistance of cancer cells via the inhibition of BCRP-mediated drug efflux as well as the down-regulation of BCRP expression.
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Metadata
Title
Discovery of LW6 as a new potent inhibitor of breast cancer resistance protein
Authors
Jae Guen Song
Yeo Song Lee
Jin-Ah Park
Eun-Hye Lee
Soo-Jeong Lim
Seung Jun Yang
Mengjia Zhao
Kyeong Lee
Hyo-Kyung Han
Publication date
01-10-2016
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 4/2016
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-016-3127-2

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