Histamine H₁ Receptor Antagonists in Cancer: Mechanisms, Clinical Evidence, and Therapeutic Potential

Articles in Press

Document Type : review article

Authors

1 Student Research Committee, Faculty of Medicine, Mashhad Medical Sciences, Islamic Azad University, Mashhad, Iran

2 Clinical Research Development Unit of Akbar hospital, Mashhad university of medical sciences, Mashhad, Iran

10.22038/jpp.2025.91948.5605

Abstract

Histamine's signaling through histamine H1 receptor (H1R) plays an important role in cancer biology. H1R is overexpressed in numerous malignancies and assists with proliferation, invasion, angiogenesis and evasion of the immune system. Given the widespread use of H1 antihistamines in the treatment of allergic diseases, there is a growing interest in the incorporation of these agents as anticancer therapy. Preclinical studies have demonstrated a role for H1- antagonists both in the apoptosis, pyroptosis, lysosomal destabilization, and reversal of multidrug resistance, and in the enhancement of chemotherapy and immunotherapy efficacy. Specific agents such as loratadine, desloratadine, and cyproheptadine have demonstrated survival benefits upon administrations for breast, ovarian, lung, and hepatocellular cancers but the evidence is inconsistent. This inconsistency could be attributed to dosing, drug class, target tumor and study design. First-generation antihistamines show strong mechanistic activity but limited tolerability. In contrast second- and third-generation drugs are safer but require higher doses than usual therapeutic ranges. Although H1 antihistamines have been demonstrated to have several mechanisms that can be utilized for therapeutic purposes in oncology, sufficient randomized clinical trials and clinical evidence have yet to emerge. Crucial questions for clinical application such as defining optimal agents, dosing strategies, and synergistic combinations with chemotherapy or immunotherapy are not yet fully answered.

Keywords

Journal of Pediatric Perspectives

Articles in Press, Accepted Manuscript
Available Online from 25 November 2025

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