Doxazosin induces apoptosis of cells expressing hERG K+ channels

Abstract

The antihypertensive drug doxazosin has been associated with an increased risk for congestive heart failure and cardiomyocyte apoptosis. Human ether-a-go-go-related gene (hERG) K(+) channels, previously shown to be blocked by doxazosin at therapeutically relevant concentrations, represent plasma membrane receptors for the antihypertensive drug. To elucidate the molecular basis for doxazosin-associated pro-apoptotic effects, cell death was studied in human embryonic kidney cells using three independent apoptosis assays. Doxazosin specifically induced apoptosis in hERG-expressing HEK cells, while untransfected control groups were insensitive to treatment with the antihypertensive agent. An unexpected biological mechanism has emerged: binding of doxazosin to its novel membrane receptor, hERG, triggers apoptosis, possibly representing a broader pathophysiological mechanism in drug-induced heart failure.

Human ether-�-go-go-related gene expression is essential for cisplatin to induce apoptosis in human gastric cancer

“…HERG is overexpressed in a wide range of human cancers, such as gastric cancer, colorectal cancer, endometrial cancer and glioblastoma multiforme (11)(12)(13)(14). Three main functions relevant to tumor cell biology can be ascribed to HERG activity: tumor cell proliferation (15), tumor cell invasiveness (12) and tumor neoangiogenesis (16). Because of their oncogenic properties, distribution, modulation and pharmacology, HERG has gained great interest as potential diagnostic markers and membrane therapeutic targets for cancer (17,18).…”

Blocking of the Human Ether-à-go-go-Related Gene Channel by Imatinib Mesylate

“…14,16) It has been reported that calcium channel blocking can compensate for the proarrhythmic effects of the HERG blockade. 27,28) Nonetheless, our findings provide a direct cellular mechanism for IM-induced QT interval prolongation and cardiac arrhythmia. Direct inhibition of the HERG channel may be of greater concern when IM is used in patients with congenital long QT syndrome, in patients with electrolyte abnormalities such as hypokalemia, or in patients receiving other QT intervalprolonging drugs.…”

Mechanisms of zolpidem‐induced long QT syndrome: acute inhibition of recombinant hERG K+ channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells

“…Pro-apoptotic effects have been observed with low-affinity hERG current inhibitors (Thomas et al, 2008;Gong et al, 2010;Obers et al, 2010;Staudacher et al, 2011a). In contrast, zolpidem did not affect apoptosis of HL-1 cardiac myocytes.…”

“…Pharmacological inhibition of hERG channels has been shown to promote apoptosis (Thomas et al, 2008;Obers et al, 2010;Jehle et al, 2011;Staudacher et al, 2011a). To assess whether zolpidem exerts similar actions, apoptotic cell death was studied in HL-1 cells using TUNEL staining (Figure 7).…”

“…In addition to the heart, hERG potassium channels are expressed in tumour cells where they are involved in the regulation of cell proliferation and apoptosis (Bianchi et al, 1998;Cherubini et al, 2000;Smith et al, 2002;Wang et al, 2002). Recently, inhibition of cardiac hERG channels has been revealed to promote apoptosis, suggesting a novel mechanism of cardiotoxicity (Thomas et al, 2008;Gong et al, 2010;Obers et al, 2010;Staudacher et al, 2011a). In contrast to electrophysiological effects of hERG current reduction leading to LQTS, hERGassociated apoptosis may contribute to cardiomyocyte loss and heart failure.…”