The major goal of the proposed research is to develop a novel high throughput method for evaluating the cardiac liability of anticancer drugs. In recent years, more and more adverse cardiac events have been linked to the use of non-cardiac drugs. An important example of an anticancer drug with this association is arsenic trioxide, used for the treatment of relapsed or refractory acute promyelocytic leukemia. Arsenic trioxide causes QT prolongation and torsade de pointes. It is important that the cardiac liability of anticancer drugs be recognized so that (1) patients can be carefully monitored for ECG changes, (2) electrolyte imbalances and unfavorable interactions with other medications can be avoided, and (3) alternative treatment strategies can be considered. The cardiac potassium channel hERG is a frequent target of unwanted drug interactions, often leading to acquired long QT syndrome in patients. This is often, but not always, due to acute channel block. We have found that the cell surface expression of hERG is significantly reduced by exposure to two inhibitors of the chaperone Hsp90 that are currently undergoing clinical trials as anticancer drugs, geldanamycin and radicicol. Neither drug is an acute hERG blocker. We propose that therapeutic drugs may not only produce cardiotoxic side effects by acute channel block but also by compromising the biosynthesis and trafficking of cardiac ion channels and transporters.
The specific aims of this proposal are to: 1) develop a high throughput method for evaluating the cardiac liability of anticancer compounds and establish proof of principle of our method for a major repolarizing cardiac current; and 2) extend the method to other ion channels and transporters that contribute to cardiac repolarization.
| Wang, Lu; Wible, Barbara A; Wan, Xiaoping et al. (2007) Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking. J Pharmacol Exp Ther 320:525-34 |
| Kuryshev, Yuri A; Wang, Lu; Wible, Barbara A et al. (2006) Antimony-based antileishmanial compounds prolong the cardiac action potential by an increase in cardiac calcium currents. Mol Pharmacol 69:1216-25 |
| Kuryshev, Yuri A; Ficker, Eckhard; Wang, Lu et al. (2005) Pentamidine-induced long QT syndrome and block of hERG trafficking. J Pharmacol Exp Ther 312:316-23 |
| Ficker, Eckhard; Dennis, Adrienne; Kuryshev, Yuri et al. (2005) HERG channel trafficking. Novartis Found Symp 266:57-69; discussion 70-4, 95-9 |
| Wible, Barbara A; Hawryluk, Peter; Ficker, Eckhard et al. (2005) HERG-Lite: a novel comprehensive high-throughput screen for drug-induced hERG risk. J Pharmacol Toxicol Methods 52:136-45 |
| Thomas, Dierk; Hammerling, Bettina C; Wimmer, Anna-Britt et al. (2004) Direct block of hERG potassium channels by the protein kinase C inhibitor bisindolylmaleimide I (GF109203X). Cardiovasc Res 64:467-76 |
