Submitted on December 11, 2008
Revised on February 5, 2009
Accepted on February 19, 2009
State-dependent block of HERG potassium channels by R-roscovitine: Implications for cancer therapy
Sindura B Ganapathi1, Mark Kester2, and Keith S Elmslie1*
1 Penn State College of Medicine
2 The Pennsylvania State University
* To whom correspondence should be addressed. E-mail: kse10{at}psu.edu.
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 anti-arrhythmic 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 over expressed both in multiple tumor cell lines and primary tumor cells, which makes HERG an attractive target for cancer treatment. Therefore, a drug that can block HERG, but does not induce cardiac arrhythmias would have great therapeutic potential. Roscovitine is a cyclin-dependent kinase 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 (HEK293 cells stably expressing HERG) at clinically relevant concentrations. The block (IC50 = 27 µM) was rapid (
= 20 ms) and reversible ( = 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.
