The Role Of Antihistamines In Cancer Therapy

ANTIHISTAMINES

Specific antihistamines taken during chemo- or immunotherapy are reported to improve treatment response and measurably slow down progression. Often, with an effect similar to adding a second oncology drug. Also while reducing unwanted side effects from both drugs and inflammation. Collectively, research results indicate using desloratadine for early stage or localized cancers and loratadine for advanced stages. There are examples where alternatives such as ebastine or others show up National patient databases in Scandinavia have several studies in this area, with focus on cancers responsive to immunotherapy. These studies observe that antihistamines improve and balance immune system activity. Desloratadine is shown as protective for all localized cancers in this “immunogenic” group, some have relative risk reductions above 25%.

Also notable, loratadine was effective in ovarian cancer even in non or weakly-immunogenic types. The benefits are strongest for post-diagnostic use, particularly during active treatment phases like chemotherapy or immunotherapy. In breast cancers a dedicated analysis showed both HER+ and HER- patients saw over 30% risk reduction with desloratadine. Again showing the importance of selection, ebastine had even more surprising benefits in the range of 70% relative risk reductions in post-menopausal breast cancers (see References). A recent data analysis of cyproheptadine with tyrosine kinase inhibitor sorafenib reported more than doubled survival times for advanced liver cancers.

A large study in non-localized/ metastatic cases histories reports loratadine, ebastine and desloratadine users with 20% or more reduced risks following chemotherapy. And mapped the mechanisms in lab tests as proof of action. The focus was on advanced stage lung cancer where only loratadine and ebastine are identifed as effective with chemotherapy – and resulting in 30 to 40% positive effects. For these tumor types, use of desloradine also showed sustained effects on the long term absolute survival rates over 2 to 4 year time periods over 10%, which is in itself similar to the outcomes of immunotherapy drugs.

Emerging research is reporting that antihistamines can increase immunotherapy response rate. For instance in lung cancer, users of diphenhydramine get in a large 2 to 3X improvement in overall and progression free periods. Confirmation can be seen in a new analysis of patient data for immunotherapy patients in Turkish oncology who saw more than double the relative survival rate receiving anti-histamines during treatment. And a summary review looking across the six highest quality studies and over 4000 cases finds ALL of these publications show reduced risks.

Allergies are often shown to reduce cancer incidence, thought to be related to hightened immune system activity. Post-diagnosis though, pre-existing allergies with high histamine levels can impair cancer patients’ anti-tumor immune response during treatment The reduced oncology impacts are most clear in melanoma and lung cancers. Histamine is implicated in research as a driver of cancer growth and in particular metastasis. Studies show histamine being one mechanism by which cancer stem cells can evade oncology treatments. An anti-inflammatory diet reducing histamine heavy food sources has been shown to reduce cancer progress

Long term use of anti-histamines pre-diagnosis show variable effects, some cancers see lower risk. However, meta-analysis also show slightly elevated risks with prostate, breast and other cancers including glioma. (see Examples). Speculative use to reduce cancer incidence is not proposed in research studies.

ANTI-METASTATIC ACTIONS

TYPICAL ABSORPTION LEVELS

High

EXAMPLES OF IMPROVED OUTCOMES

YES

PRE-DIAGNOSIS OR PREVENTION

MIXED

Highlighted Studies

..there is already a compelling case for further studies of H₁-antihistamines as potential cancer treatment, as well as for initiation of clinical trials of mainly desloratadine and loratadine, as treatment of both breast cancer and cutaneous malignant melanoma..that pool should be extended to include at least all other immunogenic tumors in our study and priority should be given to trials of desloratadine as treatment of tumor types with dismal prognoses. The potential gain in pro...

Data presented above suggest that addition of clinically relevant doses of well-tolerated CAD antihistamines to the standard cancer chemotherapy regiment improves cancer prognosis. This conclusion is based on statistically significant inverse associations between the use of loratadine, or the use of either loratadine or astemizole, and all-cause mortality among Danish patients with non-localized NSCLC or any non-localized cancer, respectively. Furthermore, ebastine use was associated with red...

…cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival…histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction….antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response…Importantly, cancer patients with low plasma histamine levels had a more than tripled objective re...

Desloratadine in particular stands out as a candidate forcancer therapy based on our findings, and its known prop-erties: it has the highest H1-receptor affinity among theseantihistamines, outperforming fexofenadine and other com-pounds in pharmacokinetic studies [21]. Worth noting isthat our findings are based on the use of antihistaminesto treat allergies, and it remains to be seen what a thera-peutic dose of desloratadine as a drug for the treatmentof breast cancer may be, though we suspec...

TABLE OF REFERENCES

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URL	Rating	Category	Highlight	Highlight 2
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868613/	5	Human study	We believe that there is already a compelling case for further studies of H1-antihistamines as potential cancer treatment, as well as for initiation of clinical trials of mainly desloratadine and loratadine, as treatment of both breast cancer and cutaneous malignant melanoma. Based on what we present here, that pool should be extended to include at least all other immunogenic tumors in our study and priority should be given to trials of desloratadine as treatment of tumor types with dismal prognoses. The potential gain in prognosis, with treatments with little or no toxicity, could be substantial, especially for patients who currently have few treatment options	Our hypothesis is that our findings result from immune checkpoint inhibition, and we believe both desloratadine and loratadine should be tested in randomized clinical trials as treatment of immunogenic tumors, with priority given to trials of desloratadine as treatment of tumors with few therapy options and dismal prognoses, such as pancreatic cancer. If our results can be confirmed in a clinical setting, new, potentially curative, therapies could result for several tumors, including ones with dire prognoses and limited treatment options.
https://www.thelancet.com/article/S2352-3964(16)30257-2/fulltext	5	Human study - adjunct	Cationic amphiphilic drugs (CADs) induce lysosomal membrane permeabilization and cell death preferentially in cancer cells. Here, we show that antihistamines with CAD structure, i.e. astemizole, ebastine and loratadine, sensitize cancer cells to chemotherapy and revert multidrug resistance even at low, clinically relevant concentrations. The significance of these experimental findings is supported by an association between CAD antihistamine use and reduced mortality among patients diagnosed with non-localized cancer, especially among those receiving concurrent chemotherapy. These findings are immediately translatable to clinical trials, as loratadine and ebastine, are safe, inexpensive and approved for clinical use.	The use of the most commonly prescribed CAD antihistamine, loratadine, was associated with significantly reduced all-cause mortality among patients with non-localized NSCLC or any non-localized cancer when compared with use of non-CAD antihistamines ... the association between CAD antihistamine use and reduced mortality was stronger among patients with records of concurrent chemotherapy than among those without such records. In line with this, sub-micromolar concentrations of loratadine, astemizole and ebastine sensitized NSCLC cells to chemotherapy and reverted multidrug resistance in NSCLC, breast and prostate cancer cells. Thus, CAD antihistamines may improve the efficacy of cancer chemotherapy.
https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00602-4	5	Meta-analysis, Lab study- adjunct	Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. Importantly, cancer patients with low plasma histamine levels had a more than tripled objective response rate to anti-PD-1 treatment compared with patients with high plasma histamine. Altogether, pre-existing allergy or high histamine levels in cancer patients can dampen immunotherapy responses and warrant prospectively exploring antihistamines as adjuvant agents for combinatorial immunotherapy.	Our finding that plasma histamine levels of, and uptake of antihistamines by, cancer patients are associated with their response to immunotherapy strongly supports using antihistamines to treat cancer patients who have allergy with high levels of plasma histamine. OTC H1-antihistamines can restore T cell function suppressed by cancer cell-secreted and/or allergy-released histamine and improve the efficacy of immunotherapies such as ICB therapies. Our findings necessitate further clinical studies to prospectively test the effect of H1-antihistamines as adjuvant therapies for enhancing immunotherapy responses in cancer patients.
https://www.tandfonline.com/doi/full/10.1080/0284186X.2020.1769185#	5	Human study - adjunct, Human study	We found a consistently improved survival of desloratadine ...as well as of loratadine users... regardless of patient age, menopause, estrogen receptor status or stage of the tumor, or whether breast cancer-specific or overall survival was analyzed. The survival of users of other antihistamines varied relative to non-users......we suggest the initiation of trials of desloratadine and loratadine as treatment of breast cancer as well as studies of the mechanism behind their possible effect. Further studies on any effects of other H1-antihistamines may also be merited, as well as of H1-antihistamine use and survival in other malignancies	the results for ebastine and fexofenadine were usually non-significant (although the point estimates for ebastine were positive, and in postmenopausal women, ebastine use was associated with a markedly improved – and statistically significant – survival with HR = 0.32). Desloratadine and loratadine use was consistently associated with a better survival for women with both ER positive and negative tumors, though the results for loratadine were not always statistically significant. Among postmenopausal women, both desloratadine and loratadine users had a pronouncedly improved survival, however, for premenopausal women, the results were not statistically significant
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492759/	5	Human study, Lab study	In our cohort study, CAD antihistamine use (≥1 prescription; n = 133) was associated with a hazard ratio of 0.63 (95% CI = 0.40 to 0.99) compared to use of non-CAD antihistamines (n = 304), and we found a tendency toward a dose-response association. In our cell viability assay, we found consistent and dose-dependent cytotoxicity for all CAD but not non-CAD antihistamines. In this nationwide cohort study, use of antihistamines with CAD characteristics is associated with a prognostic benefit in ovarian cancer patients.	In conclusion, in a nationwide cohort study, we provide epidemiologic evidence suggesting that antihistamines with CAD characteristics at current doses may provide a prognostic benefit in ovarian cancer patients. The plausibility of this finding was confirmed in vitro in ovarian cancer cell lines. Further efforts are required to confirm our results in other study populations, and to elucidate the precise biological mechanism. Given that current antihistamines are well-tolerated (2), inexpensive, and already commonly used in cancer patients, CAD antihistamines may become promising candidates as adjuvants to standard ovarian cancer treatment and, therefore, merit further research.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376992/	5	Human study - adjunct	Our results indicate that cyproheptadine in combination with sorafenib prolonged the OS and PFS of sorafenib-treated advanced HCC cases. The percentage of patients with partial response or stable disease in the combination group was almost twice that in the control group. In contrast, the probability of sorafenib dose reduction was reduced by approximately half in the combination group compared with the sorafenib control group. The sorafenib–cyproheptadine combination may provide a prospective future for advanced HCC. However, this study was only a retrospective study. A prospective clinical trial with a larger sample size is needed for further investigation.	Considering the cost and benefit, this combination may produce a more advantageous and much less adverse effects compared with sorafenib alone. Furthermore, we wonder the addition of cyproheptadine to early or intermediate-stage HCC treatments could also prove beneficial; we are planning a prospective randomized clinical trial to test this hypothesis. In addition, the mechanism of cyproheptadine in HCC also requires further investigation.
https://jeccr.biomedcentral.com/articles/10.1186/s13046-023-02914-8	5	Human study - adjunct	A key finding of our study is that lung cancer patients receiving loratadine exhibit improved survival outcomes. Significant differences were observed in OS curves and PFS curves between patients with and without loratadine use. As the loratadine dose increased, patients experienced a significant improvement in outcomes. The results from animal experiments also conformed to the clinical outcomes, suggesting dose-dependent improvement. Our findings not only align with but also expand upon previous research.	A critical discovery was that high-dose loratadine augmented the PPARγ level, which subsequently spurred GSDMD transcription by our luciferase reporter assay. This finding is further substantiated by reports in the literature indicating that PPARγ is instrumental in the regulation of caspase-8 activation [25]. Tumor sections from animal models, stained for Ki67 and GSDMD, reinforce the hypothesis that loratadine hampers tumor proliferation by promoting pyroptosis. Collectively, these results highlight a novel mechanism by which loratadine may exert anti-tumoral effects through the induction of pyroptosis.
https://www.ejcancer.com/article/S0959-8049(22)00426-9/abstract	5	Meta-analysis	A total of 734 ICI-treated patients were included. After matching, 68 cationic amphiphilic antihistamine and non-cationic amphiphilic antihistamine users remained for analysis. Compared with non-cationic amphiphilic antihistamine users, patients who received cationic amphiphilic antihistamines had a significantly longer median overall survival (24.8 versus 10.4 months)	The use of cationic amphiphilic antihistamines was associated with an approximately 50% lower risk of all-cause mortality (HR, 0.55 [95% CI: 0.34–0.91]). Survival benefits were not seen in patients who received cationic amphiphilic antihistamines before immune checkpoint blockade. These survival benefits were observed regardless of the generation of cationic amphiphilic antihistamines.
https://pubmed.ncbi.nlm.nih.gov/37707624/	5	Meta-analysis	We matched 28 cationic amphiphilic [mostly loratadine, desloratadine] antihistamine users [pancreatic cancer patients] with 56 non-cationic amphiphilic antihistamine users. Cationic amphiphilic antihistamine users showed significantly longer OS (median 16.4 [IQR, 2.8 - 89.0] vs.5.8 [IQR, 2.0 - 9.8] months; p<0.001) and PFS (median 12.2 [IQR, 2.2 - 83.3] vs. 5.2 [IQR, 1.7 - 8.4] months; p=0.002) compared to non-users	the use of cationic amphiphilic antihistamines was associated with approximately 60% lower risk of all-cause mortality and disease progression. Additionally, cationic amphiphilic antihistamine users exhibited a significantly greater ORR than non-users (39% vs. 7%, p=0.004).
https://www.nature.com/articles/s41416-023-02364-1	5	Meta-analysis	Moreover, compared to men without AACs [allergies], men with AACs but without antihistamine use showed a statistically significant 23% reduction (HR = 0.77) in prostate cancer-specific mortality, while men with antihistamine use showed a 31% reduction in prostate cancer-specific mortality (HR = 0.69) and a 13% reduction in all-cause mortality (HR = 0.87)	Among men who took antihistamines, those who reported 2–5 years of use at baseline showed a non-significant increased risk of total prostate cancer compared to those with less than 1 year of use (HR = 1.21) ..Antihistamine use for 2–5 years was associated with significant or borderline significant increases in low grade (HR = 1.42) and localised prostate cancer (HR = 1.28). However, these associations were not observed in men with over 5 years of antihistamine use. E-DII [inflammatory diets] was not associated with prostate cancer incidence , but was non-significantly associated with an increased risk of metastatic prostate cancer
https://www.sciencedirect.com/science/article/abs/pii/S1078143924010470	5	Meta-analysis	In conclusion, using individual patient data from the IMvigor 210 and 211 trials, we found that concomitant use of antihistamines was associated with prolonged progression-free, cancer-specific and overall survival in patients treated with atezolizumab. Our results showed a positive association between antihistamines use and oncologic outocmes in patients with [bladder cancer] mUC treated with IO.	Concomitant antihistamines administration was associated with improved OS, CSS, and PFS in patients receiving atezolizumab as second line treatment for mUC. Further mechanistic and clinical investigation is warranted to elucidate the role of antihistamines in IO.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8779329/	4.5	Meta-analysis, Human study - adjunct	Among the forty common drugs examined, only HRH1-specific antihistamines (H1-antihistamines or second-generation antihistamines) significantly correlated with better survival of patients besides aspirin (Figure 1A). Clearly, melanoma patients who took H1-antihistamines during anti-PD-1/PD-L1 treatments had a highly significantly reduced death rate than did age-, sex-, or stage-matched patients without taking the H1-antihistamines (Figures 1B, 1C, S1B and Table S2). Among lung cancer patients receiving anti-PD-1/PD-L1 treatments, those taking H1-antihistamines also showed a statistically significant reduction of death rate	Importantly, cancer patients with low plasma histamine levels had more than tripled objective response rate to anti-PD-1 treatment compared to patients with high plasma histamine. Altogether, pre-existing allergy or high histamine levels in cancer patients can dampen immunotherapy responses and warrant prospectively exploring antihistamines as adjuvant agents for combinatorial immunotherapy.
https://tlcr.amegroups.org/article/view/92203/html	4.5	Human study - adjunct	The median progression-free survival (mPFS) was 12.7 months in the experimental group and 4.3 months in the control group, while the median overall survival (mOS) was 32.8 months in the experimental group and 18.1 months in the control group. In the experimental group, patients treated with only H1 antihistamines had longer mPFS and mOS compared with those who received H1 plus H2 antihistamines. Similarly, in the control group, patients who did not receive antihistamines had a longer mPFS and mOS than those who only received H2 antihistamines. After conducting multivariate analyses, we found that H1 and H2 antihistamines were respectively identified as good and poor independent prognostic factors for both progression-free survival (PFS) and overall survival (OS). The rates of irAEs in the experimental and control groups were 52.4% and 69.2%, respectively, and grade ≥3 irAEs occurred in 4.5% and 25.9% of patients, respectively.	Further subgroup analyses were conducted (Figure 4). Analysis of PFS (Figure 4A) indicated that, in the experimental group, patients treated with only H1 antihistamine (n=40) had a longer PFS compared to those who received H1 plus H2 antihistamines (n=69) after IPTW (18.0 vs. 6.8 months; HR 0.40, 95% CI: 0.26–0.63; P<0.001). In the control group, patients who received no antihistamine (n=75) had a longer PFS than those who received only H2 antihistamines (n=27) after IPTW (5.8 vs. 4.1 months; HR 0.44, 95% CI: 0.29–0.67; P<0.001). Analysis of OS (Figure 4B) revealed that, in the experimental group, patients treated with only H1 antihistamine had a longer OS than those who received H1 plus H2 antihistamines after IPTW (not reached vs. 26.6 months; HR 0.55, 95% CI: 0.32–0.94, P=0.03). In the control group, patients who received no antihistamines had a longer OS than those who received only H2 antihistamines after IPTW (25.2 vs. 16.9 months; HR 0.61, 95% CI: 0.37–1.00, P=0.049). These results showed that H1 antihistamine may improve the efficacy of ICI immunotherapy, whereas H2 antihistamine could potentially diminish its effectiveness.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10695773/	4.5	Meta-analysis	The ESCC-specific mortality rate was also higher in the non-AH1 group (77.99%) compared to the AH1 group (58.25%). The use of AH1 after beginning standard CCRT was found to have a significant impact on all-cause mortality in patients with ESCC. An analysis of the data revealed that the adjusted hazard ratio (aHR) for all-cause mortality in the group of patients who used AH1 was 0.52 when compared to the group of patients who did not use AH1	Our study results suggest that the incorporation of AH1 during the course of CCRT may enhance overall survival and ESCC-specific survival among patients receiving definitive CCRT for ESCC. Furthermore, our study revealed that a higher cumulative dose (cDDD) of AH1 use was associated with a decrease in all-cause mortality and ESCC-specific mortality. An optimal daily intensity of 0.84 defined daily dose (DDD) of AH1 use was identified as having the lowest ESCC-specific mortality. These findings provide evidence that the use of AH1 during CCRT may enhance outcomes for patients with ESCC
https://pubmed.ncbi.nlm.nih.gov/38018837/	4.5		The median progression-free survival (PFS) (8.2 vs. 5.1 months) and overall survival (OS) (16.2 vs. 7.7 months) were longer in patients receiving antihistamines concomitantly with ICIs. In multivariate analysis, PFS [hazard ratio (HR) = 0.63] and OS (HR = 0.49) were also better in those patients after adjusting for confounding factors, such as performance status, bone or liver metastasis, and concurrent chemotherapy. This study suggested that antihistamines may enhance the efficacy of ICIs in patients with advanced cancer.	Histamine and H1 receptors play a crucial role in the tumor microenvironment. Preclinical data showed that concomitant use of antihistamines and immune checkpoint inhibitors (ICIs) might increase the effect of ICIs. This study aimed to evaluate the impact of antihistamines on the oncological outcomes of ICIs. This retrospective study was conducted in a tertiary cancer center. Advanced cancer patients treated with ICIs were included in this study. A total of 133 patients receiving ICIs in the metastatic setting were included. Melanoma (33.1%) was the most common tumor type.
https://onlinelibrary.wiley.com/doi/10.1002/cam4.70583	4.5	Meta-analysis	In conclusion, our findings are, by and large, in line with previous studies suggesting that H1-antihistamines could be promising adjuvants to enhance ICI responses in patients with lung malignancies. Unfortunately, H1-antihistamine use may increase mortality risk in patients with liver malignancies. The increased mortality risk in intermediate or frequent users might suggest that underlying chronic allergic inflammation poses challenges to restoring ICI response. We observed that third-generation H1-antihistamines could be independently associated with a reduction in mortality risk among all patients	A total of 1740 (65.1% male, mean age 61.9 years) were included in the landmark analysis, of which 529 (30.4%) and 307 (17.6%) had primary lung and liver malignancies. The multivariable Cox regression model estimated statistically significant improvement in overall survival of intermediate use in patients with primary lung malignancies (adjusted hazard ratio [aHR] 0.223, 95% confidence interval [CI] 0.052–0.958, p = 0.044), but not with primary liver maligancies. Similar frequency-dependent effects were identified in Kaplan–Meier analysis.
https://www.cureus.com/articles/326618-the-impact-of-antihistamines-on-immunotherapy-a-systematic-review#!/	4	Meta-analysis	The combination of antihistamines with immunotherapy represents a promising approach to the treatment of cancer. As immunotherapies continue to reshape cancer treatment and as we begin to investigate alternative uses for everyday medications, antihistamines may propose beneficial effects on improving the efficacy of immunotherapy. Novel findings all indicate the positive effects immunotherapy in combination with antihistamines have on overall survival and progression-free survival states. While more research is needed to confirm these benefits and understand the underlying mechanisms, this combination approach holds considerable promise for improving patient outcomes and advancing the way we treat cancer.	Furthermore, antihistamines are divided into cationic and non-cationic amphiphilic antihistamines. Cationic antihistamines have been found to have greater anticancer effects when compared to non-cationic amphiphilic antihistamines. Cationic amphiphilic antihistamines are defined by their hydrophobic ring structure and hydrophilic side chain with a cationic amine group. When placed in an acidic environment, such as a lysosome, the basic amine group gets pronated and leads to a significant accumulation. When cationic antihistamines enter the lysosome, they inhibit lysosomal lipases by neutralizing the negative charge; specifically, they inhibit sphingomyelinase leading to sphingomyelin accumulation, which is toxic to cancer cells [36-39]. Cationic antihistamines, including desloratadine, cyproheptadine, ebastine, loratadine, and astemizole, have been found to be associated with greater overall survival and longer progression-free survival when compared to non-cationic amphiphilic antihistamines
https://journals.lww.com/anti-cancerdrugs/abstract/2024/02000/impact_of_antihistamine_use_on_the_survival.8.aspx	4	Meta-analysis	A total of 133 patients receiving ICIs in the metastatic setting were included. Melanoma (33.1%) was the most common tumor type. The most common ICI was nivolumab (63.2%). Fifty-five (38.4%) patients received antihistamines concomitantly with ICIs. The most common antihistamine was pheniramine (85.5%). The median progression-free survival (PFS) (8.2 vs. 5.1 months) and overall survival (OS) (16.2 vs. 7.7 months) were longer in patients receiving antihistamines concomitantly with ICIs. I	In multivariate analysis, PFS [hazard ratio (HR) = 0.63, 95% CI: 0.40–0.98, P = 0.042] and OS (HR = 0.49, 95% CI: 0.29–0.81, P = 0.006) were also better in those patients after adjusting for confounding factors, such as performance status, bone or liver metastasis, and concurrent chemotherapy. This study suggested that antihistamines may enhance the efficacy of ICIs in patients with advanced cancer.
https://www.cureus.com/articles/326618-the-impact-of-antihistamines-on-immunotherapy-a-systematic-review#!/	4	Meta-analysis	The combination of antihistamines with immunotherapy represents a promising approach to the treatment of cancer. As immunotherapies continue to reshape cancer treatment and as we begin to investigate alternative uses for everyday medications, antihistamines may propose beneficial effects on improving the efficacy of immunotherapy. Novel findings all indicate the positive effects immunotherapy in combination with antihistamines have on overall survival and progression-free survival states.	When analyzing the findings of the articles, all articles found a significant improvement in overall survival rates and longer progression-free rates when antihistamines were added to immunotherapy regimens compared to patients who did not utilize antihistamines. Additionally, some studies also analyzed mortality rates, and each found a significant reduction in mortality rates when antihistamines were paired with immunotherapy [19,20,22]. Interestingly, Chiang et al. found that specifically cationic amphiphilic antihistamines improved outcomes to a greater extent than non-cationic amphiphilic antihistamines [
https://www.nature.com/articles/s41388-019-1093-y#Sec2	3.5	Human study, Meta-analysis	H1 histamine receptor (H1HR) belongs to the family of rhodopsin-like G-protein-coupled receptors. Recent studies have shown that H1HR expression is increased in several types of cancer. However, its functional roles in tumor progression remain largely unknown, especially in hepatocellular carcinoma (HCC). We found that H1HR is frequently unregulated in HCC, which is significantly associated with both recurrence-free survival and overall survival in HCC patients. Functional experiments revealed that H1HR promoted both the growth and metastasis of HCC cells by inducing cell cycle progression	...the association between allergies and cancer risk is complex, the risk of developing cancer could depend on the specific malignancy, and H1HR may be a feasible target in cancer prevention. However, the potential use of H1HR antagonists to treat liver cancer has been unexplored until now. Our data clearly showed that TF treatment significantly inhibited the growth and metastasis of HCC both in vitro and in vivo, indicating that inhibition of H1HR by TF may be a promising novel therapeutic strategy for treating HCC.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392479/	2	Meta-analysis	...histamine is highly implicated in cancer development, growth, and metastasis through interactions with distinct [ Histamine Receptors ]. It also regulates the infiltration of immune cells into the tumor sites, exerting an immunomodulatory function. Moreover, the effects of various HR ligands, including H1R antagonists, H2R antagonists, and H4R agonists, on tumor progression in many different cancer types are described. Interestingly, the expression levels of HR subtypes may serve as prognostic biomarkers in several cancers. Taken together, HRs are promising targets for cancer treatment, and HR ligands may offer novel therapeutic potential, alone or in combination with conventional therapy	All of these findings, along with their known safety profiles as medicines in current use, have triggered human clinical trials with H1R antagonists. Indeed, several studies have been published showing improved OS of cancer patients taking H1R antagonists: MM [139] and BC [140] with the use of loratadine and desloratadine, and NSCLC [141] and OC [135] with the use of some cationic amphiphilic antihistamine drugs (CAD). Overall, these in vitro and in vivo studies, as well as several human trials, have revealed a substantial relationship between cancer regression and H1R antagonists, supporting the potential use of H1R antagonists in combination with traditional therapy to improve their therapeutic efficacy and/or impede the development of resistance to therapy.
https://www.embopress.org/doi/full/10.15252/emmm.201809034	1	Lab study	In a preclinical model, treatment of glioma-bearing mice with an antihistaminergic [Lysosomal Membrane Permeabilization]-inducing drug efficiently eradicated invasive glioma cells and secondary tumours within the brain. This unexpected fragility of the aggressive infiltrating cells to LMP provides new opportunities for clinical interventions, such as re-positioning of an established antihistamine drug, to eradicate the inoperable, invasive, and chemo-resistant glioma cells from sustaining disease progression and recurrence.	The inoperable, highly invasive and chemo-resistant glioma stem cell-like cells showed an unexpected fragility towards LMP. Thus, our study provides a potential answer to the clinical challenge for the management of the cells that eventually will lead to the recurrence of the disease. These results also suggest re-positioning of an old drug with a new indication. More widely, LMP-inducing agents should be considered as a possible novel treatment option for gliomas.
https://aacrjournals.org/mct/article/19/10/2023/274241/Antihistamine-Drug-Ebastine-Inhibits-Cancer-Growth	1	Lab study	In this study, we first discovered ebastine, an antihistamine drug for allergy treatment, as a potent EZH2 inhibitor by targeting the promoter of EZH2, which downregulates both mRNA and protein levels of EZH2. It has been previously reported that the mRNA and protein levels of EZH2 are associated with the neoplastic properties in many cancers (6, 8–14). We consistently demonstrated that ebastine effectively inhibits the proliferation, migration	Altogether, our results revealed that ebastine could be a promising therapeutic intervention for cancers bearing EZH2 overexpression or mutations. A retrospective study reported that patients with breast cancer taking ebastine for allergy treatment had a better overall and breast cancer–specific survival rate compared with those not taking antihistamine drugs (48–50), further suggesting the safety and the potential of using ebastine in clinical settings
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10130003/	1	Lab study	[Ebastine] treatment induced apoptosis and a sharp decline in the expression of the BCSC markers ALDH1, CD44 and CD49f, suggesting that EBA targets BCSC-like cell populations while reducing tumor bulk. EBA administration significantly impeded BCSC-enriched tumor burden, angiogenesis and distant metastasis while reducing MMP-2/-9 levels in circulating blood in vivo. Our findings suggest that EBA may represent an effective therapeutic for the simultaneous targeting of JAK2/STAT3 and MEK/ERK for the treatment of molecularly heterogeneous TNBC with divergent profiles. Further investigation of EBA as an anti-metastatic agent for the treatment of TNBC is warranted.	[Ebastine] administration in vivo retarded tumor growth, angiogenesis and lung metastasis in BCSC-enriched allografts. Of particular note, the anti-metastatic and anti-angiogenic properties of EBA was attributable to significant decreases in MMP-2 and MMP-9 serum levels. The matrix metalloproteinases facilitate tumor neovascularization and metastatic spread via the degradation and remodeling of ECM. MMP-2/-9 serum levels were significantly escalated in metastatic allograft mice when compared to normal BALB/c mice of the same age, however, these effects were abolished following EBA treatment in vivo
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830506/	1	Lab study, Lab study- adjunct	These results indicated that ebastine (a H1-histamine receptor antagonist) exerts antitumor activity in osteosarcoma. Ebastine exerts an antitumor effect and promotes autophagy by activating the AMPK/ULK1 signaling pathway, which is IPMK dependent. Our results provide insight into the clinical application potential of ebastine and indicate that ebastine might be a novel candidate to treat osteosarcoma patients	We first detected the antitumor properties of ebastine on osteosarcoma..the results illustrated that ebastine inhibited the proliferation and metastasis of osteosarcoma. Additionally, flow cytometry assays demonstrated that ebastine induced cell cycle arrest in S phase and promoted the apoptosis of osteosarcoma cells. In the subcutaneous tumor model, the size and weight of tumors were significantly decreased in response to treatment with ebastine. Simultaneously, in the lung metastasis model, there was a significant decrease in lung metastases in the ebastine group. Moreover, there were no obvious toxic effects of ebastine in the animal experiments
https://www.nature.com/articles/s41392-022-01248-9/	1	Lab study	In addition, desloratadine markedly increased apoptosis of HCC cells and reduced the volume of tumor xenografts in animal models. Our results showed that desloratadine inhibited the progression of HCC through suppressing the enzyme activity of NMT1. Other factors may be involved in the anticancer effect of desloratadine and the underlying mechanism may be further investigated. More importantly, preclinical studies in PDO and PDX models further confirmed the anticancer of desloratadine in suppressing HCC progression	Our present study indicated that treatment with desloratadine can sensitize HCC cells to traditional chemotherapeutic drugs. In summary, we demonstrated that NMT1 promotes HCC tumorigenesis by enhancing the myristoylation and stability of the VILIP3 protein. Desloratadine directly binds to NMT1 to suppress the progression of HCC by inhibiting the enzymatic activity of NMT1 and subsequent VILIP3/NFκB/Bcl-2 signaling (Fig. 6h). These findings not only highlight the potential of NMT1 as a prognostic biomarker and therapeutic target in HCC but also support the use of desloratadine in cancer treatment.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352610/	1	Lab study	Deptropine also inhibited the processing of cathepsin L from its precursor form to its mature form. Immunofluorescence microscopy showed an increase of autophagosomes in deptropine-treated cells, but deptropine blocked the fusion between autophagosomes and lysosomes. In a xenograft nude mice model, 2.5 mg/kg deptropine showed a great inhibitory effect on Hep3B tumor growth. These results suggest that deptropine can induce in vitro and in vivo hepatoma cell death, and the underlying mechanisms might be mediated through inhibiting autophagy by blocking autophagosome-lysosome fusion.	Deptropine also significantly inhibited HCC tumor growth in a xenograft nude mice model.... results suggest that deptropine can induce cell death through interfering with the process of autophagy in HCC. Our findings of inhibition of autophagy and induction of hepatoma cell death by deptropine, suggesting that deptropine and other structural-analogue drugs might be potential drugs for clinical treatment of hepatoma.
https://www.spandidos-publications.com/10.3892/or.2019.7119	1		It was observed that [Histamine Receptor]H3 was significantly upregulated in HCC tissues, while its expression was significantly associated with recurrence‑free survival and overall survival in HCC patients. Functional experiments also demonstrated that HRH3 upregulation facilitated the growth and metastasis of HCC cells by inducing the formation of lamellipodia. These findings revealed that HRH3 serves an important role in the growth and metastasis of HCC cells, which provides experimental evidence supporting the application of HRH3 as a potential therapeutic target in HCC treatment.	The prognostic significance of HRH3 was also assessed in the 96 HCC patients based on the IHC data from the tumor tissues. Kaplan-Meier survival analysis revealed that HCC patients with high HRH3 expression had significantly shorter OS and RFS as compared with those in patients exhibiting low HRH3 expression.. Taken together, these data indicated that HRH3 contributes to the progression and poor prognosis of HCC.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10188024/	1	Lab study- adjunct	In both cell lines, sorafenib, raloxifene, and loratadine in two-drug and three-drug combinations significantly reduced metabolic activity and significantly increased the percentage of apoptotic cells compared to the single-drug effect. In addition, all the combinations significantly reduced the colony-forming capacity in the HepG2 cell line. Surprisingly, the effect of raloxifene on apoptosis was similar to that observed using the combinations. Conclusion: The triple combination sorafenib-raloxifene-loratadine may be a novel promising approach in the treatment of liver cancer patients.	Some antihistamines have gained enormous interest as potential anticancer drugs. In retrospective studies with patients diagnosed with different types of cancer including breast cancer and melanoma, Fritz et al. found that the use of the antihistamine loratadine and its metabolite desloratadine, was associated with improved overall survival (20,21). Noteworthy, Ellegaard et al. found that the use of loratadine in patients diagnosed with lung cancer was associated with a significant reduction in mortality, but desloratadine had no a significant effect (7). They suggested that the strong sensitization of the lysosomal membrane in cancer cells allows the entry of cationic amphiphilic drugs (CADs), including loratadine, to this organelle leading to cell death
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8835856/	1	Lab study, Lab study- adjunct	HNMT [Histamine metabolism enzyme] upregulation in NSCLC [Lung cancer] cells may upregulate HER2 expression, increasing tumorigenicity and chemoresistance through CSCs maintenance and antioxidant properties. This newly discovered regulatory axis may aid in retarding NSCLC progression and chemoresistance	..HNMT upregulation in NSCLC cells leads to HER2 upregulation, which in turn increases tumorigenicity and chemoresistance through CSCs maintenance and antioxidant properties. This CSCs may downregulate miR-3065-5p and miR-223 expression, thus reducing the inhibition of their target gene, HNMT, thereby resulting in a feedback loop that may aid in maintaining the CSCs population of NSCLC and conferring chemoresistance