title: Novel multidrug-resistance modulators, KR-30026 and KR-30031, in cancer cells.
abstract: The present study was performed to evaluate the ability of KR-30026 and KR-30031 to overcome multidrug resistance (MDR) by measuring the cytotoxicity of paclitaxel and the rate of rhodamine accumulation, which were then compared with verapamil. KR-30026 potentiated the paclitaxel-induced cytotoxicity of HCT15 to over 60 fold greater than that of verapamil, and KR-30031 was equipotent with verapamil (EC50: 0.00066, 0.04 and 0.05 nM at 4.0 micrograms/ml, respectively). KR-30026 and KR-30031 were without effect on paclitaxel-induced cytotoxicity to SK-OV-3 cells, as well as on tamoxifen-induced cytotoxicity to HCT15, HCT15/CL02 and SK-OV-3 cells. Maximal rhodamine accumulation by KR-30026, KR-30031 and verapamil were similar in HCT15 cells, while KR-30026 was more potent than verapamil in HCT15/CL02 cells (721 and 440%, respectively). To evaluate the cardiac toxicity of KR-30026 and KR-30031, the changes of tension in isolated rat aorta and left ventricular pressure (LVP) in guinea pig heart were determined; KR-30026 and KR-30031 were 15-40 and 25-70 fold less potent than verapamil, respectively. These results suggest that KR-30026 and KR-30031 are active modulators of MDR with potentially minimal cardiovascular toxicity.
authors.affiliation: Screening and Toxicology Research Center, Korea Research Institute of Chemical Technology, Yusong, Taejon, Seoul, Korea.
authors.forename: S U
authors.initials: SU
authors.lastname: Choi
authors.forename: B H
authors.initials: BH
authors.lastname: Lee
authors.forename: K H
authors.initials: KH
authors.lastname: Kim
authors.forename: E J
authors.initials: EJ
authors.lastname: Choi
authors.forename: S H
authors.initials: SH
authors.lastname: Park
authors.forename: H S
authors.initials: HS
authors.lastname: Shin
authors.forename: S E
authors.initials: SE
authors.lastname: Yoo
authors.forename: N P
authors.initials: NP
authors.lastname: Jung
authors.forename: C O
authors.initials: CO
authors.lastname: Lee
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects*; D015179:Colorectal Neoplasms; D018432:Drug Resistance, Multiple; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D010051:Ovarian Neoplasms; D017239:Paclitaxel / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012235:Rhodamines / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured; D014664:Vasodilation / Q000187:drug effects*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012235:Rhodamines; D014700:Verapamil; D017239:Paclitaxel