Antihistamine to reverse immunosuppressive mechanism in cancer

Histamine is produced in the human body by some of the white blood cells called basophils, eosinophils, and by mast cells found especially numerous at sites of potential injury €” the nose, mouth, and feet, internal body surfaces, and blood vessels. Its role is to increase the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues. Histamine is known to be involved in many physiological functions because of its chemical properties that allow it to be versatile in binding. Ref

“Histamine has multiple effects on both innate and adaptive immune responses, mediated by the four histamine receptors (H1€“H4). In relation to cancer, histamine is associated with an immunosuppressive tumour microenvironment, including an increase in CD4+CD25+ regulatory T cell (Treg) activity, reduced antigen-presenting activity of dendritic cells (DC), reduced NK-cell activity and increased myeloid-derived suppressor cell (MDSC) activity” Ref

A recent research report suggests that antihistamines may have significant anti-cancer properties as they interfere with the function of a type of cell that is known to reduce the body’s ability to fight tumors. Antihistamine used in this study are common drugs such as Cimetidine and Cetirizine Ref.

Here is the study:

Mast cell histamine promotes the immunoregulatory activity of myeloid-derived suppressor cells http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056279/

Abstract: It has been shown recently that MCs are required for differential regulation of the immune response by granulocytic versus monocytic MDSCs. Granulocytic MDSCs promoted parasite clearance, whereas monocytic MDSCs enhanced tumor progression; both activities were abrogated in MC-deficient mice. Herein, we demonstrate that the lack of MCs also influences MDSC trafficking. Preferential trafficking to the liver was not seen in MC-deficient mice. In addition, evidence that the MC mediator histamine was important in MDSC trafficking and activation is also shown. MDSCs express HR1€“3. Blockade of these receptors by HR1 or HR2 antagonists reversed the histamine enhancement of MDSC survival and proliferation observed in cell culture. In addition, histamine differentially influenced Arg1 and iNOS gene expression in MDSCs and greatly enhanced IL-4 and IL-13 message, especially in granulocytic MDSCs. Evidence that histamine influenced activity seen in vitro translated to in vivo when HR1 and HR2 antagonists blocked the effect of MDSCs on parasite expulsion and tumor metastasis. All of these data support the MDSC-mediated promotion of Th2 immunity, leading to the suggestion that allergic-prone individuals would have elevated MDSC levels. This was directly demonstrated by looking at the relative MDSC levels in allergic versus control patients. Monocytic MDSCs trended higher, whereas granulocytic MDSCs were increased significantly in allergic patients. Taken together, our studies indicate that MCs and MC-released histamine are critical for MDSC-mediated immune regulation, and this interaction should be taken into consideration for therapeutic interventions that target MDSCs.

Indeed Cimetidine, a H2 receptor antagonist, is known to have important anti cancer capabilities, on of the main mechanism being via the modulation of the immune system Ref

A concomitant blockade of both H1 and H2 as an anti cancer strategy (with Cimetidine and Cetirizine) may be even wiser to revers various immunosuppressive mechanism.

Another H1 receptor antagonist with known aticancer effects is Terfenadine:
Terfenadine induces anti-proliferative and apoptotic activities in human hormone-refractory prostate cancer through histamine receptor-independent Mcl-1 cleavage and Bak up-regulation
Terfenadine-induced apoptosis in human melanoma cells is mediated through Ca2+ homeostasis modulation and tyrosine kinase activity, independently of H1 histamine receptors

Desloratadine a H1 receptor antagonist was also recently found to have anti cancer activity: “This population based registry study shows that women treated with second generation antihistamines have a better overall and BC specific survival compared with non users regardless of age, history of allergy, ER status and tumor stage. The results are strongest for desloratadine use and use after BC diagnosis. Second generation antihistamines could offer a nontoxic therapy for both receptor positive and negative BC. The mechanism behind this effect is presently unknown.” http://meeting.ascopubs.org/cgi/content/abstract/33/15_suppl/3062

Antihistamines ‘reversed tumor-enhancing effects of myeloid-derived suppressor cells’

 

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Emad
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Emad

I am using chloroquine with my mother , but I read about possible interaction with cimetidine

http://www.drugs.com/interactions-check.php?drug_list=593-0,669-0

I hope to use them both together