Ether-a-go-go 1 (EAG1) potassium channels are overexpressed in the majority of cancers and inhibition of their activity has been shown to decrease tumor growth and migration. Here, we show that an FDA-approved tricyclic drug amitriptyline (AmiT) inhibits EAG1 by binding to their regulatory intracellular Per-Arnt-Sim (PAS) domains and exerts EAG1-dependent anti-tumorigenic effects. AmiT inhibited the proliferation of breast cancer MDA-MB-231 and neuroblastoma SH-SY5Y cancer cells known to express EAG 1 channels at high levels, while having a smaller effect on the proliferation of melanoma A375 cells expressing EAG1 at lower levels. Consistent with these findings, overexpression of EAG1 channels in HEK293 cells increased the anti-proliferative effect of AmiT, while knocking out EAG1 in MDA-MB-231 cells decreased the anti-proliferative effect of the drug. AmiT also inhibited cell migration in MDA-MB-231 and SH-SY5Y cells, while having no effect in A375 cells. Knocking out EAG1 in MDA-MB-231 cells completely removed the effect of AmiT on cell migration. Similar to the in vitro results, AmiT inhibited tumor growth for MDA-MB-231 and SH-SY5Y zebrafish xenografts, while having no effect on the tumor growth for A375 zebrafish xenografts. Taken together, these results indicate that EAG1 channels are a functional target of AmiT and suggest a potential repurposing of this FDA-approved drug as an anti-cancer agent for tumors with high EAG1 expression. AmiT is an antidepressant that is also used for pain management in cancer patients, suggesting that AmiT treatment could provide a double benefit for cancer patients.
Berghausen et al. (Sun,) studied this question.