title: State-dependent block of HERG potassium channels by R-roscovitine: implications for cancer therapy.
abstract: Human ether-a-go-go-related gene (HERG) potassium channel acts as a delayed rectifier in cardiac myocytes and is an important target for both pro- and antiarrhythmic drugs. Many drugs have been pulled from the market for unintended HERG block causing arrhythmias. Conversely, recent evidence has shown that HERG plays a role in cell proliferation and is overexpressed both in multiple tumor cell lines and in primary tumor cells, which makes HERG an attractive target for cancer treatment. Therefore, a drug that can block HERG but that does not induce cardiac arrhythmias would have great therapeutic potential. Roscovitine is a cyclin-dependent kinase (CDK) inhibitor that is in phase II clinical trials as an anticancer agent. In the present study we show that R-roscovitine blocks HERG potassium current (human embryonic kidney-293 cells stably expressing HERG) at clinically relevant concentrations. The block (IC(50) = 27 microM) was rapid (tau = 20 ms) and reversible (tau = 25 ms) and increased with channel activation, which supports an open channel mechanism. Kinetic study of wild-type and inactivation mutant HERG channels supported block of activated channels by roscovitine with relatively little effect on either closed or inactivated channels. A HERG gating model reproduced all roscovitine effects. Our model of open channel block by roscovitine may offer an explanation of the lack of arrhythmias in clinical trials using roscovitine, which suggests the utility of a dual CDK/HERG channel block as an adjuvant cancer therapy.
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Milton S. Hershey Medical Center, 500 University Dr., Hershey, PA 17033, USA.
authors.forename: Sindura B
authors.initials: SB
authors.lastname: Ganapathi
authors.forename: Mark
authors.initials: M
authors.lastname: Kester
authors.forename: Keith S
authors.initials: KS
authors.lastname: Elmslie
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000378:metabolism; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D007700:Kinetics; D008564:Membrane Potentials; D008955:Models, Cardiovascular; D009154:Mutation; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D011687:Purines / Q000494:pharmacology* / Q000633:toxicity; D000077546:Roscovitine; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases