title: Differential effects of the optical isomers of KR30031 on cardiotoxicity and on multidrug resistance reversal activity.
abstract: The present study was performed to compare the cardiovascular adverse effects of verapamil, KR30031 and their optical isomers, and also to measure their ability to overcome multidrug resistance (MDR). The R-isomer of KR30031 (R-KR30031) was equipotent with the S-isomer of KR30031 (S-KR30031) and 25-fold less potent than the R-isomer of verapamil (R-verapamil) in relaxing the aorta isolated from rat (EC50: 11.8, 10.2 and 0.46 microM, respectively). The effect of R-KR30031 in decreasing left ventricular pressure of heart isolated from rat was 2- and 267-fold smaller than those of S-KR30031 and R-verapamil, respectively (EC50: 23.9, 9.4 and 0.089 mM, respectively). The hypotensive effect of R-KR30031 in rat was about 2- and 23-fold smaller than those of S-KR30031 and R-verapamil, respectively (ED20: 1.15, 0.60 and 0.05 mg/kg, respectively). On the other hand, R-KR30031 elicited potency similar to those of S-KR30031 and R-verapamil in enhancing the paclitaxel-induced cytotoxicity to HCT15/CL02 and MES-SA/DX5 cells that reveal high levels of P-glycoprotein expression (IC50: 3.11, 3.04 and 2.58 microM, respectively). In addition, the intrinsic cytotoxicity of R-KR30031 in HCT15/CL02 and MES-SA/DX5 cells was observed only at the very high concentration of 100 microM. All these results suggest that R- and racemic KR30031 are active modulators of MDR with potentially minimal cardiovascular adverse activity.
authors.affiliation: Medicinal Science Division, Korea Research Institute of Chemical Technology, Taejon, Republic of Korea.
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lee
authors.forename: Chong Ock
authors.initials: CO
authors.lastname: Lee
authors.forename: Myung-Ja
authors.initials: MJ
authors.lastname: Kwon
authors.forename: Kyu Yang
authors.initials: KY
authors.lastname: Yi
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Yoo
authors.forename: Sang-Un
authors.initials: SU
authors.lastname: Choi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000633:toxicity; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004317:Doxorubicin / Q000009:adverse effects / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007536:Isomerism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014594:Uterine Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014664:Vasodilation / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects; D014700:Verapamil / Q000031:analogs & derivatives / Q000633:toxicity*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; C476929:KR30031; D004317:Doxorubicin; D014700:Verapamil