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

Document Type : review article

Authors

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

2 Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

10.22038/jpp.2025.91948.5605

Abstract

Histamine signaling through the histamine H1 receptor (H1R) plays a significant role in cancer biology. H1R is often overexpressed various malignancies and contributes to 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 incorporating these agents as anticancer therapy. Preclinical studies have demonstrated a role for H1- 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 H1 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.

Keywords

References

  1. Fritz I, Wagner P, Broberg P, Einefors R, Olsson H. Desloratadine and loratadine stand out among common H1-antihistamines for association with improved breast cancer survival. Acta Oncologica. 2020 Sep 1;59(9):1103-9.
  2. Leurs R, Smit MJ, Timmerman H. Molecular pharmacological aspects of histamine receptors. Pharmacology & therapeutics. 1995 Jan 1;66(3):413-63.
  3. Thurmond RL, Gelfand EW, Dunford PJ. The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines. Nature reviews Drug discovery. 2008 Jan;7(1):41-53.
  4. Trybus E, Trybus W. H1 Antihistamines—Promising Candidates for Repurposing in the Context of the Development of New Therapeutic Approaches to Cancer Treatment. Cancers. 2024 Dec 20;16(24):4253.
  5. Ellegaard AM, Dehlendorff C, Vind AC, Anand A, Cederkvist L, Petersen NH, et al. Repurposing cationic amphiphilic antihistamines for cancer treatment. EBioMedicine. 2016 Jul 1;9:130-9.
  6. Liu X, Zhong R, Huang J, Chen Z, Xu H, Lin L, et al. Loratidine is associated with improved prognosis and exerts antineoplastic effects via apoptotic and pyroptotic crosstalk in lung cancer. Journal of Experimental & Clinical Cancer Research. 2024 Jan 2;43(1):5.
  7. Feng YM, Feng CW, Lu CL, Lee MY, Chen CY, Chen SC. Cyproheptadine significantly improves the overall and progression-free survival of sorafenib-treated advanced HCC patients. Japanese Journal of Clinical Oncology. 2015 Apr 1;45(4):336-42.
  8. Mallardo D, Simeone E, Vanella V, Vitale MG, Palla M, Scarpato L, et al. Concomitant medication of cetirizine in advanced melanoma could enhance anti-PD-1 efficacy by promoting M1 macrophages polarization. Journal of Translational Medicine. 2022 Sep 30;20(1):436.
  9. Massari NA, Nicoud MB, Medina VA. Histamine receptors and cancer pharmacology: an update. British journal of pharmacology. 2020 Feb;177(3):516-38.
  10. Or CH, Su HL, Lee WC, Yang SY, Ho C, Chang CC. Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo. Oncology Reports. 2016 Dec 1;36(6):3465-71.
  11. Yadav P, Vengoji R, Jain M, Batra SK, Shonka N. Pathophysiological role of histamine signaling and its implications in glioblastoma. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer. 2024 Sep 1;1879(5):189146.
  12. Zhao J, Hou Y, Yin C, Hu J, Gao T, Huang X, et al. Upregulation of histamine receptor H1 promotes tumor progression and contributes to poor prognosis in hepatocellular carcinoma. Oncogene. 2020 Feb 20;39(8):1724-38.
  13. Ding YF, Ho KH, Lee WJ, Chen LH, Hsieh FK, Tung MC, et al. Cyclic increase in the histamine receptor H1-ADAM9-Snail/Slug axis as a potential therapeutic target for EMT-mediated progression of oral squamous cell carcinoma. Cell Death & Disease. 2025 Mar 20;16(1):191.
  14. Zhong P, Nakata K, Oyama K, Higashijima N, Sagara A, Date S, et al. Blockade of histamine receptor H1 augments immune checkpoint therapy by enhancing MHC-I expression in pancreatic cancer cells. Journal of Experimental & Clinical Cancer Research. 2024 May 8;43(1):138.
  15. Nguyen PL, Cho J. Pathophysiological roles of histamine receptors in cancer progression: implications and perspectives as potential molecular targets. Biomolecules. 2021 Aug 18;11(8):1232.
  16. Wake H, Hatipoglu OF, Nishinaka T, Watanabe M, Toyomura T, Mori S, et al. Histamine induces vascular endothelial cell proliferation via the histamine H1 receptor–extracellular regulated protein kinase 1/2–cyclin D1/cyclin-dependent kinase 4/6 axis. Microvascular Research. 2025 Sep 3:104866.
  17. Sarasola MD, Taquez Delgado MA, Nicoud MB, Medina VA. Histamine in cancer immunology and immunotherapy. Current status and new perspectives. Pharmacology Research & Perspectives. 2021 Oct;9(5):e00778.
  18. Olsson HL. Use of certain antihistamines among breast cancer patients confers survival benefit. Cancer Research. 2018 Jul 1;78(13_Supplement):5695-.
  19. Fritz I, Wagner P, Olsson H. Improved survival in several cancers with use of H1-antihistamines desloratadine and loratadine. Translational oncology. 2021 Apr 1;14(4):101029.
  20. Fujimura R, Asada A, Aizawa M, Kazama I. Cetirizine more potently exerts mast cell-stabilizing property than diphenhydramine. Drug Discoveries & Therapeutics. 2022 Oct 31;16(5):245-50.
  21. Asuaje A, Martín P, Enrique N, Zegarra LA, Smaldini P, Docena G, et al. Diphenhydramine inhibits voltage-gated proton channels (Hv1) and induces acidification in leukemic Jurkat T cells-New insights into the pro-apoptotic effects of antihistaminic drugs. Channels. 2018 Jan 1;12(1):58-64.
  22. Won DH, Yu HJ, Cho NP, Cho SD. In vitro Apoptotic Effect of Terfenadine in Human Oral Cancer Cells Via the Regulation of Caspase 8 and Bid. 대한구강악안면병리학회지. 2015 Apr;39(2):473-8.
  23. Verdoodt F, Dehlendorff C, Jäättelä M, Strauss R, Pottegård A, Hallas J, et al. Antihistamines and ovarian cancer survival: nationwide cohort study and in vitro cell viability assay. JNCI: Journal of the National Cancer Institute. 2020 Sep;112(9):964-7.
  24. Hamid O, Hamidi N. Enhancing immuno-oncology efficacy with H1-antihistamine in cancer therapy: A review of current research and findings. Current Medical Research and Opinion. 2024 Dec 1;40(12):2139-46.
  25. Lisiecka MZ. Evolution, mechanism of action, and clinical applications of three generations of Antihistamines. Innovaciencia. 2024 Aug 16;12(1).
Journal of Pediatric Perspectives
Volume 13, Issue 12
December 2025
Pages 19827-19834

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