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

Histamine signaling through the histamine H۱ receptor (H۱R) plays a significant role in cancer biology. H۱R is often overexpressed various malignancies and contributes to proliferation, invasion, angiogenesis and evasion of the immune system. Given the widespread use of H۱ antihistamines in the treatment of allergic diseases, there is a growing interest in incorporating these agents as anticancer therapy. Preclinical studies have demonstrated a role for H۱- antagonists in apoptosis, pyroptosis, lysosomal destabilization, and reversal of multidrug resistance, as well as in enhancing chemotherapy and immunotherapy efficacy. Specific agents such as loratadine, desloratadine, and cyproheptadine have demonstrated survival benefits in 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 H۱ antihistamines have demonstrated 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.

کلیدواژه ها:

Antihistamines ، Cancer therapy ، Drug repurposing ، Histamine H۱ receptor