title: Reversal of multidrug resistance by novel verapamil analogs in cancer cells.
abstract: The present study was performed to evaluate the ability of KR-30032 and KR-30035 to overcome multidrug resistance (MDR) by measuring the cytotoxicity and the accumulation rate of rhodamine. Additionally, the adverse cardiac toxicity of KR-30032 and KR-30035 was evaluated by measuring the changes of tension in isolated rat aorta and left ventricular pressure (LVP) in guinea pig heart. KR-30035 potentiated the paclitaxel-induced cytotoxicity to HCT15 [P-glycoprotein (P-gp)-expressed cells] to over 15-fold greater than that of verapamil and KR-30032 was equipotent with verapamil (EC50: 0.07, 5.0 and 3.3 nM at 1.0 microg/ml). KR-30032 and KR-30035 were without effect on cytotoxicity to SK-OV-3 cells (P-gp-non-expressing cells), as well as to tamoxifen-induced cytotoxicity in the above cell types. Maximal rhodamine accumulation rates with KR-30032, KR-30035 and verapamil were 290, 291 and 271% in HCT15 cells; and 451, 970 and 440% in HCT15/CL02 cells, respectively. KR-30032 and KR-30035 were 20- to 25-fold less potent than verapamil in relaxing aorta (EC50: 8.13, 6.40 and 0.32 microM, respectively) and were 12- to 35-fold less potent than verapamil in decreasing LVP in isolated hearts (EC50: 41.8, 14.1 and 1.2 microM, respectively). The results of this study suggest that KR-30032 and KR-30035 are active modulators of MDR with potentially minimal cardiovascular toxicity.
authors.affiliation: Screening and Toxicology Research Center, Korea Research Institute of Chemical Technology, Yusong, Korea.
authors.forename: S U
authors.initials: SU
authors.lastname: Choi
authors.forename: C O
authors.initials: CO
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: B H
authors.initials: BH
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000737:chemistry*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005456:Fluorescent Dyes; D006168:Guinea Pigs; D006801:Humans; D007192:Indenes / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012235:Rhodamines; D013764:Tetrahydronaphthalenes / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014700:Verapamil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D005456:Fluorescent Dyes; D007192:Indenes; C111620:KR 30032; C111621:KR 30035; D012235:Rhodamines; D013764:Tetrahydronaphthalenes; D014700:Verapamil