title: Reversal of P-glycoprotein mediated multidrug resistance in K562 cell line by a novel synthetic calmodulin inhibitor, E6.
abstract: The overexpression of P-glycoprotein (P-gp) is associated with multidrug resistance (MDR) of tumor cells to a number of chemotherapeutic drugs. P-gp inhibitors have been shown to effectively reverse P-gp-mediated MDR in both in vitro and in vivo. Our previous studies demonstrated that E6, a novel synthetic calmodulin inhibitor, exhibited potent inhibitory effect on P-gp in rat brain microvessel endothelial cells (RBMECs). In the present study, the effect of E6 on MDR in a K562 MDR cell line (K562/DOX) highly expressing P-gp was studied and compared with that of a conventional P-gp inhibitor, verapamil (VER). E6 at concentrations of 1, 3, 10, 30 microM reduced the IC50 value of doxorubicin in K562/DOX cells from 79.19 microM to 35.18, 21.86, 6.31 and 1.97 microM, respectively. However, the IC50 value of doxorubicin in K562 sensitive subline was not significantly changed by E6. Using a DNA content analysis and an annexin V binding assay, the effects of E6 on doxorubicin-induced apoptosis were also examined. The results indicated that E6 effectively reversed the resistance to doxorubicin-induced apoptosis in K562/DOX cells. In addition, co-treatment of E6 and doxorubicin resulted in a remarkably G2/M blocking effect in K562/DOX cells. Furthermore, the treatment of K562/DOX cells with 10 microM E6 led to increased intracellular accumulation and decreased efflux of doxorubicin. Overall, the pharmacological effects of E6 on P-gp-mediated MDR is much stronger than that of positive control drug VER. These results suggested that E6 is a novel and potent MDR reversal agent and may be a potential adjunctive agent for tumor chemotherapy.
authors.affiliation: Department of Pharmaceutical Sciences, Medical University of South Carolina, USA. zhuh@musc.edu
authors.forename: Hao-Jie
authors.initials: HJ
authors.lastname: Zhu
authors.forename: Jun-Sheng
authors.initials: JS
authors.lastname: Wang
authors.forename: Qing-Long
authors.initials: QL
authors.lastname: Guo
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology; D044182:Benzylisoquinolines / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D006801:Humans; D020014:K562 Cells
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D044182:Benzylisoquinolines; D002147:Calmodulin; C488276:E6 isoquinoline; D004317:Doxorubicin