Uncovering the mechanism of action of cardiac arrhythmias caused by cancer therapeutics that target the hERG channel: A Literature review
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Over the years, tremendous progression in development of cancer treatments has taken place with more cancer survivors as a result. As more cancer-survivors live with the long-term effects of the cancer treatments and will eventually deal with age-related diseases such as cardiovascular diseases, the cardiovascular risk factors are magnified, and complications may lead to morbidity and mortality in cancer survivors. Anticancer drugs can lead to drug-induced arrhythmias by either direct or indirect changes, where the former could lead to the inhibition of the rapid component of the delayed rectifier K+ channel (IKr) which prolongs the QTc interval and eventually to the life-threatening ventricular arrhythmia Torsades de Pointes (TdP). The inhibition of IKr is related to the blockage of the human etherà-go-go related gene (hERG) potassium channel as this channel plays a role in the repolarization of the heart ventricles. Gaining more knowledge about the binding mechanisms of the different chemotherapeutic drugs that target this channel may help the development of new chemotherapeutic agents without the adverse cardiotoxicity. In this review, the mechanism by which the hERG channel is inhibited by several chemotherapeutic drugs was assessed. The two mechanisms to inhibit the hERG channel are by either binding to the F656 and/or Y652 aromatic residues in the binding pocket of hERG, creating a direct blockage of the channel, or inhibiting the trafficking of the fully glycosylated hERG channels to the cell surface by inhibiting the hERG-Hsp90 complex formation. Further research should be performed to elucidate the exact molecules that bind to the residues in the binding pocket and Hsp90 inhibition, which may lead to hERG channel degradation, should be accounted for when developing new chemotherapeutic agents. Agents that target the hERG channel, but do not induce arrhythmias, should still be carefully monitored in older patients as they have an increased risk of proarrhythmogenic events. Elucidating the mechanism of the inhibition will make the development of new chemotherapeutic agents safer, even for the aging population.