H1 Antihistamines-Promising Candidates for Repurposing in the Context of the Development of New Therapeutic Approaches to Cancer Treatment

Abstract

Despite significant progress in the field of clinical oncology in terms of diagnostic and treatment methods, the results of anticancer therapy are still not fully satisfactory, especially due to limited response and high toxicity. This has forced the need for further research to finding alternative ways to improve success rates in oncological treatment. A good solution to this problem in the context of rapidly obtaining an effective drug that works on multiple levels of cancer and is also safe is the global strategy of repurposing an existing drug. Research into other applications of an existing drug enables a precise assessment of its possible mechanisms of action and, consequently, the broadening of therapeutic indications. This strategy is also supported by the fact that most non-oncological drugs have pleiotropic effects, and most of the diseases for which they were originally intended are multifactorial, which in turn is a very desirable phenomenon due to the heterogeneous and multifaceted biology of cancer. In this review, we will mainly focus on the anticancer potential of H1 antihistamines, especially the new generation that were not originally intended for cancer therapy, to highlight the relevant signaling pathways and discuss the properties of these agents for their judicious use based on the characteristic features of cancer.

Keywords: H1-antyhistamines drugs; alternative cell death pathways; apoptosis; cancer therapy; cancer tumor microenvironment; cell resistance; drug repurposing; histamine; non-receptor mechanisms.

Figure 1

H1 receptor inverse agonists [105,158,159].

Figure 2

The pathways regulating the CAD-induced cell death pathway [181,182,209]. A-SMase—acid sphingomyelinase, SM—sphingomyelin, P2X4—pH-sensitive purinergic receptor, ADCY1—adenylate cyclase 1, CADs—cationic amphiphilic antihistamines, LMP—lysosomal membrane permeabilization, LCD—lysosomal cell death.