Mortality-to-incidence ratio in cancer patients is extremely high, positioning cancer as a major cause of death worldwide. Despite hundreds of clinical trials for anti-cancer drugs that are currently in progress, most clinical trials for novel drug treatments fail to pass Phase I. However, previously developed drugs with novel anti-tumor properties offer a viable and cost-effective alternative to fight cancer. Histamine favors the proliferation of normal and malignant cells. Several anti-histamine drugs, including astemizole, can inhibit tumor cell proliferation. Astemizole has gained enormous interest since it also targets important proteins involved in cancer progression, namely, ether a-go-go 1 (Eag1) and Eag-related gene (Erg) potassium channels. Furthermore, Eag1 is thought to be an important marker and a therapeutic target for several different cancers. Astemizole inhibits Eag1 and Erg channel activity, and in cells expressing the Eag1 channel it decreases tumor cell proliferation in vitro and in vivo. It should be noted that some cardiovascular side effects have been reported for astemizole in a few rare cases. Nevertheless, astemizole stands as a very promising anti-cancer tool because it displays several anti-proliferative mechanisms, may serve as the basis to synthesize new anti-cancer agents, and has been previously administered clinically. In this review we will summarize the main findings relating to histamine and anti-histamines in cancer cell proliferation focusing on astemizole targets (Eag1 and Erg channels), and its anti-cancer effects in vitro and in vivo. We will also describe the side effects of astemizole and discuss proposals to overcome such effects in cancer patients. Finally, we will remark on the relevance of developing novel astemizole-related compounds.
Keywords: Anticancer drugs, Astemizole, Eag1, Erg, Histamine, Potassium channels, QT-interval, PHARMACOKINETICS, Diphenydramine, Cardiotoxicity, IC50, EAG1 channel inhibitors, colon carcinoma
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