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

• Published in: Cancer chemotherapy and pharmacology 2016-10, Vol.78 (4), p.735-744
• Main Authors: Song, Jae Guen, Lee, Yeo Song, Park, Jin-Ah, Lee, Eun-Hye, Lim, Soo-Jeong, Yang, Seung Jun, Zhao, Mengjia, Lee, Kyeong, Han, Hyo-Kyung
• Format: Article
• Language: English
• Subjects: Acetanilides - pharmacokinetics; Acetanilides - pharmacology; Acetanilides - therapeutic use; Adamantane - analogs & derivatives; Adamantane - pharmacokinetics; Adamantane - pharmacology; Adamantane - therapeutic use; Animals; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; ATP Binding Cassette Transporter, Sub-Family B - antagonists & inhibitors; ATP Binding Cassette Transporter, Sub-Family B - biosynthesis; ATP Binding Cassette Transporter, Sub-Family B - genetics; ATP Binding Cassette Transporter, Sub-Family G, Member 2 - antagonists & inhibitors; ATP Binding Cassette Transporter, Sub-Family G, Member 2 - biosynthesis; ATP Binding Cassette Transporter, Sub-Family G, Member 2 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Breast cancer; Breast Neoplasms - drug therapy; Cancer Research; Cell Line, Tumor; Cell Survival - drug effects; Drug Discovery; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Male; Medicine; Medicine & Public Health; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Oncology; Original Article; Pharmacology/Toxicology; Rats; Rats, Sprague-Dawley
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-016-3127-2

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