title: Discovery of LW6 as a new potent inhibitor of breast cancer resistance protein.
abstract: The present study aimed to discover a new potent BCRP inhibitor overcoming multidrug resistance.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: College of Pharmacy, Dongguk University-Seoul, Dongguk-ro 32, Ilsandong-gu, Goyang, Korea.
authors: Jae Guen
authors: JG
authors: Song
authors: College of Pharmacy, Dongguk University-Seoul, Dongguk-ro 32, Ilsandong-gu, Goyang, Korea.
authors: Yeo Song
authors: YS
authors: Lee
authors: College of Pharmacy, Dongguk University-Seoul, Dongguk-ro 32, Ilsandong-gu, Goyang, Korea.
authors: Jin-Ah
authors: JA
authors: Park
authors: Department of Bioscience and Bioengineering, Institute of Bioscience, Sejong University, Seoul, Korea.
authors: Eun-Hye
authors: EH
authors: Lee
authors: Department of Bioscience and Bioengineering, Institute of Bioscience, Sejong University, Seoul, Korea.
authors: Soo-Jeong
authors: SJ
authors: Lim
authors: College of Pharmacy, Dongguk University-Seoul, Dongguk-ro 32, Ilsandong-gu, Goyang, Korea.
authors: Seung Jun
authors: SJ
authors: Yang
authors: College of Pharmacy, Dongguk University-Seoul, Dongguk-ro 32, Ilsandong-gu, Goyang, Korea.
authors: Mengjia
authors: M
authors: Zhao
authors: College of Pharmacy, Dongguk University-Seoul, Dongguk-ro 32, Ilsandong-gu, Goyang, Korea.
authors: Kyeong
authors: K
authors: Lee
authors: College of Pharmacy, Dongguk University-Seoul, Dongguk-ro 32, Ilsandong-gu, Goyang, Korea. hkhan@dongguk.edu.
authors: Hyo-Kyung
authors: HK
authors: Han
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000083:Acetanilides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000218:Adamantane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000083:Acetanilides; D000970:Antineoplastic Agents; C000607696:LW6 compound; D009363:Neoplasm Proteins; D000218:Adamantane
keywords: BCRP; Cancer; Inhibitor; LW6; Multidrug resistance