Indoleamine 2,3-dioxygenase in lung dendritic cells promotes Th2 responses and allergic inflammation.
Xu Hui,Oriss Timothy B,Fei Mingjian,Henry Adam C,Melgert Barbro N,Chen Li,Mellor Andrew L,Munn David H,Irvin Charles G,Ray Prabir,Ray Anuradha
Proceedings of the National Academy of Sciences of the United States of America
Indoleamine 2,3 dioxygenase (IDO) has emerged as an important mediator of immune tolerance via inhibition of Th1 responses. However, the role of IDO in antigen-induced tolerance or allergic inflammation in the airways that is regulated by Th2 responses has not been elucidated. By using IDO(-/-) mice, we found no impairment of airway tolerance, but, surprisingly, absence of IDO provided significant relief from establishment of allergic airways disease, as evident from attenuated Th2 cytokine production, airway inflammation, mucus secretion, airway hyperresponsiveness, and serum ovalbumin-specific IgE. Myeloid dendritic cells isolated from lung-draining lymph nodes of mice immunized for either Th1 or Th2 response revealed fewer mature dendritic cells in the lymph nodes of IDO(-/-) mice. However, the net functional impact of IDO deficiency on antigen-induced responses was more remarkable in the Th2 model than in the Th1 model. Collectively, these data suggest that IDO is not required for the induction of immune tolerance in the airways but plays a role in promoting Th2-mediated allergic airway inflammation via unique effects on lung dendritic cells.
10.1073/pnas.0708809105
Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives.
Godin-Ethier Jessica,Hanafi Laïla-Aïcha,Piccirillo Ciriaco A,Lapointe Réjean
Clinical cancer research : an official journal of the American Association for Cancer Research
Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme with immune-regulating activities in many contexts, such as fetal protection, allograft protection, and cancer progression. Clinical trials are currently evaluating IDO inhibition with 1-methyltryptophan in cancer immunotherapy. However, the exact role of tryptophan catabolism by IDO in human cancers remains poorly understood. Here, we review several studies that correlate IDO expression in human cancer samples and tumor-draining lymph nodes, with relevant clinical or immunologic parameters. IDO expression in various histologic cancer types seems to decrease tumor infiltration of immune cells and to increase the proportion of regulatory T lymphocytes in the infiltrate. The impact of IDO on different immune cell infiltration leads to the conclusion that IDO negatively regulates the recruitment of antitumor immune cells. In addition, increased IDO expression correlates with diverse tumor progression parameters and shorter patient survival. In summary, in the vast majority of the reported studies, IDO expression is correlated with a less favorable prognosis. As we may see results from the first clinical trials with 1-methyltryptophan in years to come, this review brings together IDO studies from human studies and aims to help appreciate outcomes from current and future trials. Consequently, IDO inhibition seems a promising approach for cancer immunotherapy.
10.1158/1078-0432.CCR-11-1331
Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs.
Ninomiya Soranobu,Narala Neeharika,Huye Leslie,Yagyu Shigeki,Savoldo Barbara,Dotti Gianpietro,Heslop Helen E,Brenner Malcolm K,Rooney Cliona M,Ramos Carlos A
Blood
Although T cells expressing CD19-specific chimeric antigen receptors (CARs) are a promising new therapy for B-cell malignancies, objective responses are observed at lower frequencies in patients with lymphoma than in those with acute B-cell leukemia. We postulated that the tumor microenvironment suppresses CAR-expressing T cells (CARTs) through the activity of indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme that converts tryptophan into metabolites that inhibit T -: cell activity. To investigate the effects of tumor IDO on CD19-CART therapy, we used a xenograft lymphoma model expressing IDO as a transgene. CD19-CARTs inhibited IDO-negative tumor growth but had no effect on IDO-positive tumors. An IDO inhibitor (1-methyl-tryptophan) restored IDO-positive tumor control. Moreover, tryptophan metabolites inhibited interleukin (IL)-2-, IL-7-, and IL-15-dependent expansion of CARTs; diminished their proliferation, cytotoxicity, and cytokine secretion in vitro in response to CD19 recognition; and increased their apoptosis. Inhibition of CD19-CARTs was not mitigated by the incorporation of costimulatory domains, such as 4-1BB, into the CD19-CAR. Finally, we found that fludarabine and cyclophosphamide, frequently used before CART administration, downregulated IDO expression in lymphoma cells and improved the antitumor activity of CD19-CART in vivo. Because tumor IDO inhibits CD19-CARTs, antagonizing this enzyme may benefit CD19-CART therapy.
10.1182/blood-2015-01-621474
The mannose receptor negatively modulates the Toll-like receptor 4-aryl hydrocarbon receptor-indoleamine 2,3-dioxygenase axis in dendritic cells affecting T helper cell polarization.
Salazar Fabián,Hall Laurence,Negm Ola H,Awuah Dennis,Tighe Patrick J,Shakib Farouk,Ghaemmaghami Amir M
The Journal of allergy and clinical immunology
BACKGROUND:Dendritic cells (DCs) are key players in the induction and re-elicitation of TH2 responses to allergens. We have previously shown that different C-type lectin receptors on DCs play a major role in allergen recognition and uptake. In particular, mannose receptor (MR), through modulation of Toll-like receptor (TLR) 4 signaling, can regulate indoleamine 2,3-dioxygenase (IDO) activity, favoring TH2 responses. Interestingly, the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor with an emerging role in immune modulation, has been implicated in IDO activation in response to TLR stimulation. OBJECTIVE:Here we investigated how allergens and lectins modulate the TLR4-AhR-IDO axis in human monocyte-derived DCs. METHODS:Using a combination of genomics, proteomics, and immunologic studies, we investigated the role of MR and AhR in IDO regulation and its effect on T helper cell differentiation. RESULTS:We have demonstrated that LPS induces both IDO isoforms (IDO1 and IDO2) in DCs, with partial involvement of AhR. Additionally, we found that, like mannan, different airborne allergens can effectively downregulate TLR4-induced IDO1 and IDO2 expression, most likely through binding to the MR. Mannose-based ligands were also able to downregulate IL-12p70 production by DCs, affecting T helper cell polarization. Interestingly, AhR and some components of the noncanonical nuclear factor κB pathway were shown to be downregulated after MR engagement, which could explain the regulatory effects of MR on IDO expression. CONCLUSION:Our work demonstrates a key role for MR in the modulation of the TLR4-AhR-IDO axis, which has a significant effect on DC behavior and the development of immune responses against allergens.
10.1016/j.jaci.2015.10.033
Inhibition Mechanisms of Human Indoleamine 2,3 Dioxygenase 1.
Lewis-Ballester Ariel,Karkashon Shay,Batabyal Dipanwita,Poulos Thomas L,Yeh Syun-Ru
Journal of the American Chemical Society
Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) catalyze the same dioxygenation reaction of Trp to generate N-formyl kynurenine (NFK). They share high structural similarity, especially in the active site. However, hIDO1 possesses a unique inhibitory substrate binding site (Si) that is absent in hTDO. In addition, in hIDO1, the indoleamine group of the substrate Trp is H-bonded to S167 through a bridging water, while that in hTDO is directly H-bonded to H76. Here we show that Trp binding to the Si site or the mutation of S167 to histidine in hIDO1 retards its turnover activity and that the inhibited activity can be rescued by an effector, 3-indole ethanol (IDE). Kinetic studies reveal that the inhibited activity introduced by Trp binding to the Si site is a result of retarded recombination of the ferryl moiety with Trp epoxide to form NFK and that IDE reverses the effect by preventing Trp from binding to the Si site. In contrast, the abolished activity induced by the S167H mutation is primarily a result of ∼5000-fold reduction in the O binding rate constant, possibly due to the blockage of a ligand delivery tunnel, and that IDE binding to the Si site reverses the effect by reopening the tunnel. The data offer new insights into structure-based design of hIDO1-selective inhibitors.
10.1021/jacs.8b03691
Indoleamine 2,3-dioxygenase regulates anti-tumor immunity in lung cancer by metabolic reprogramming of immune cells in the tumor microenvironment.
Oncotarget
Indoleamine 2,3-dioxygenase (IDO) has been implicated in immune evasion by tumors. Upregulation of this tryptophan (Trp)-catabolizing enzyme, in tumor cells and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME), leads to Trp depletion that impairs cytotoxic T cell responses and survival; however, exact mechanisms remain incompletely understood. We previously reported that a combination therapy of gemcitabine and a superoxide dismutase mimetic promotes anti-tumor immunity in a mouse model of lung cancer by inhibiting MDSCs, enhancing polyfunctional response of CD8+ memory T cells, and extending survival. Here, we show that combination therapy targets IDO signaling, specifically in MDSCs, tumor cells, and CD8+ T cells infiltrating the TME. Deficiency of IDO caused significant reduction in tumor burden, tumor-infiltrating MDSCs, GM-CSF, MDSC survival and infiltration of programmed death receptor-1 (PD-1)-expressing CD8+ T cells compared to controls. IDO-/- MDSCs downregulated nutrient-sensing AMP-activated protein kinase (AMPK) activity, but IDO-/- CD8+ T cells showed AMPK activation associated with enhanced effector function. Our studies provide proof-of-concept for the efficacy of this combination therapy in inhibiting IDO and T cell exhaustion in a syngeneic model of lung cancer and provide mechanistic insights for IDO-dependent metabolic reprogramming of MDSCs that reduces T cell exhaustion and regulates anti-tumor immunity.
10.18632/oncotarget.12249
Targeting indoleamine-2,3-dioxygenase in cancer: Scientific rationale and clinical evidence.
Ricciuti Biagio,Leonardi Giulia Costanza,Puccetti Paolo,Fallarino Francesca,Bianconi Vanessa,Sahebkar Amirhossein,Baglivo Sara,Chiari Rita,Pirro Matteo
Pharmacology & therapeutics
Immunotherapy through immune checkpoint blockers (ICBs) is quickly transforming cancer treatment by improving patients' outcomes. However, innate and acquired resistance to ICBs remain a major challenge in clinical settings. Indoleamine 2,3-dioxygenases (IDOs) are enzymes involved in tryptophan catabolism with a central immunosuppressive function within the tumor microenvironment. IDOs are over-expressed in cancer patients and have increasingly been associated with worse outcomes and a poor prognosis. Preclinical data have shown that combining IDO and checkpoint inhibition might be a valuable strategy to improve the efficacy of immunotherapy. Currently, several IDO inhibitors have been evaluated in clinical trials, showing favorable pharmacokinetic profiles and promising efficacy. This review describes the mechanisms involved in IDO-mediated immune suppression and its role in cancer immune escape, focusing on the potential clinical application of IDO inhibitors as an immunotherapy strategy for cancer treatment.
10.1016/j.pharmthera.2018.12.004
The role of indoleamine 2,3-dioxygenase-aryl hydrocarbon receptor pathway in the TLR4-induced tolerogenic phenotype in human DCs.
Scientific reports
A controlled inflammatory response is required for protection against infection, but persistent inflammation causes tissue damage. Dendritic cells (DCs) have a unique capacity to promote both inflammatory and anti-inflammatory processes. One key mechanism involved in DC-mediated immunosuppression is the expression of tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase (IDO). IDO has been implicated in diverse processes in health and disease but its role in endotoxin tolerance in human DCs is still controversial. Here we investigated the role of IDO in shaping DCs phenotype and function under endotoxin tolerance conditions. Our data show that TLR4 ligation in LPS-primed DCs, induced higher levels of both IDO isoforms together with the transcription factor aryl-hydrocarbon receptor (AhR), compared to unprimed controls. Additionally, LPS conditioning induced an anti-inflammatory phenotype in DCs - with an increase in IL-10 and higher expression of programmed death ligand (PD-L)1 and PD-L2 - which were partially dependent on IDO. Furthermore, we demonstrated that the AhR-IDO pathway was responsible for the preferential activation of non-canonical NF-κB pathway in LPS-conditioned DCs. These data provide new insight into the mechanisms of the TLR4-induced tolerogenic phenotype in human DCs, which can help the better understanding of processes involved in induction and resolution of chronic inflammation and tolerance.
10.1038/srep43337
Indoleamine-2,3-Dioxygenase in Non-Small Cell Lung Cancer: A Targetable Mechanism of Immune Resistance Frequently Coexpressed With PD-L1.
Volaric Ashley,Gentzler Ryan,Hall Richard,Mehaffey James H,Stelow Edward B,Bullock Timothy N,Martin Linda W,Mills Anne M
The American journal of surgical pathology
The immune regulatory enzyme indoleamine-2,3-dioxygenase (IDO-1) suppresses T cell responses and may reduce efficacy of therapies targeting immune checkpoints such as programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1). Early phase clinical trials combining IDO-1 and PD-1/PD-L1 inhibitors have shown some promise in non-small cell lung cancers (NSCLCs). However, the coexpression of IDO-1 and PD-L1 has not been thoroughly investigated, and the potential for IDO-1 immunohistochemical expression as a therapeutic biomarker is unknown. One hundred two cases of NSCLC (51 adenocarcinomas, 9 adenosquamous carcinomas, and 42 squamous cell carcinomas) were evaluated for IDO-1 and PD-L1 expression by immunohistochemistry. IDO-1 expression was identified in 43% of NSCLC (42% of adenocarcinomas, 44% of adenosquamous carcinomas, and 43% of squamous cell carcinomas). Coexpression with PD-L1 (≥1%) was common (27% overall; 27% of adenocarcinomas, 33% of adenosquamous carcinomas, and 26% of squamous cell carcinomas). A smaller population of tumors showed isolated PD-L1 (25% overall; 16% of adenocarcinomas, 44% of adenosquamous carcinomas, and 33% of squamous cell carcinomas) or IDO-1 expression (15% overall; 14% of adenocarcinomas, 11% of adenosquamous carcinomas, and 17% of squamous cell carcinomas). In summary, IDO-1 is commonly expressed by NSCLC, and its frequent coexpression with PD-L1 may account for the increased efficacy seen with dual blockade of PD-1/PD-L1 and IDO in clinical studies. IDO-1 immunohistochemistry may be a useful biomarker for selection of patients who could benefit from dual-agent therapy and should be evaluated in prospective clinical trials using PD-1/PD-L1 and IDO inhibitors.
10.1097/PAS.0000000000001099
Inhibitory effects of flavonoids isolated from on indoleamine 2,3-dioxygenase 1 activity.
Kwon Mincheol,Ko Sung-Kyun,Jang Mina,Kim Gun-Hee,Ryoo In-Ja,Son Sangkeun,Ryu Hyung Won,Oh Sei-Ryang,Lee Won-Kyu,Kim Bo Yeon,Jang Jae-Hyuk,Ahn Jong Seog
Journal of enzyme inhibition and medicinal chemistry
Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan catabolising enzyme, is known as a tumour cell survival factor that causes immune escape in several types of cancer. Flavonoids of have a variety of biological benefits for humans; however, cancer immunotherapy effect has not been fully investigated. The flavonoids (1-6) isolated from showed IDO1 inhibitory activities (IC 4.331.4 µM). The representative flavonoids () of were determined to be non-competitive inhibitors of IDO1 by kinetic analyses. Their binding affinity to IDO1 was confirmed using thermal stability and surface plasmon resonance (SPR) assays. The molecular docking analysis and mutagenesis assay revealed the structural details of the interactions between the flavonoids (1-6) and IDO1. These results suggest that the flavonoids (1-6) of , especially kushenol E (), as IDO1 inhibitors might be useful in the development of immunotherapeutic agents against cancers.
10.1080/14756366.2019.1640218
Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health.
Nature medicine
The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood. Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells. However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome and may promote atherosclerosis and vascular inflammation, suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity, yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target.
10.1038/s41591-018-0060-4
Involvement of histamine in growth of mouse and rat tumors: antitumoral properties of monofluoromethylhistidine, an enzyme-activated irreversible inhibitor of histidine decarboxylase.
Bartholeyns J,Bouclier M
Cancer research
The present study suggests that newly synthesized histamine is involved in the development of some animal tumors (e.g., Lewis lung carcinoma in mice and Morris hepatoma in rats). A marked induction of histidine decarboxylase (HDC) and an increase in the histamine concentration were observed in the tumors approximately 1 week after inoculation, and there were parallel increases in ornithine decarboxylase activity and the concentrations of polyamines. The H2 receptor antagonist, cimetidine, significantly reduced tumor growth in the animal models while the H1 receptor antagonist, dexchlorpheniramine, had no effect, suggesting that histamine could act via H2 receptor sites. Extensive depletion of tumor histamine induced by local injection of Compound 48/80 did not result in a significant cytostatic effect. Monofluoromethylhistidine (MFMH), an enzyme-activated irreversible inhibitor of HDC, retarded the growth of hepatoma tissue culture cells grown in culture, and when infused s.c. at 60 mg/kg/day it greatly inhibited the development of tumors induced i.m. by hepatoma tissue culture cells in Buffalo rats. MFMH also had pronounced antitumoral effects on EMT6 sarcomas and Lewis lung carcinomas in mice, which were associated with inhibition of HDC and depletion of the histamine content of the tumors. These cytostatic effects were clearly enhanced when MFMH was combined in therapy with the specific ornithine decarboxylase inhibitor, DL-alpha-difluoromethylornithine. The antitumoral effects of the combination were associated with marked decreases in the tumor histamine and putrescine contents. It is proposed that nascent histamine, like newly synthesized putrescine and spermidine, plays a role in the rapid proliferation of animal tumors. Inhibition of HDC by essentially nontoxic drugs such as MFMH could represent a novel approach to the control of neoplastic growth.
Histamine regulates cyclooxygenase 2 gene activation through Orai1-mediated NFκB activation in lung cancer cells.
Huang Wan-Chen,Chai Chee-Yin,Chen Wei-Chiao,Hou Ming-Feng,Wang Yu-Shiuan,Chiu Yi-Ching,Lu Shiang-Ru,Chang Wen-Chang,Juo Suh-Hang Hank,Wang Jaw-Yuan,Chang Wei-Chiao
Cell calcium
Histamine, an important chemical mediator, has been shown to regulate inflammation and allergic responses. Stimulation of histamine receptors results in a significant increase in cytoplasmic Ca(2+), which could be mediated by inositol trisphosphate (IP(3))-dependent store-operated Ca(2+) channels (SOC). However, the link between histamine-mediated signaling and activation of inflammatory genes such as cyclooxygenase 2 (COX-2) is still unknown. Our study indicated that the COX-2 protein was highly expressed in human lung cancer cells. Following stimulation with 10 μM of histamine, both store-operated Ca(2+) entry (SOCE) and COX-2 gene expression were evoked. Histamine-mediated COX-2 activation can be prevented by 2-APB and SKF-96365, SOC channel inhibitors. In addition, deletion analysis of the COX-2 promoter suggested that the region between -80 bp and -250 bp, which contains NFκB binding sites, is the key element for histamine-mediated signaling. Knocking down ORAI1, one of the essential molecules of store-operated calcium channels, attenuated histamine-mediated COX-2 expression and NFκB activation. These results indicated that ORAI1-mediated NFκB activation was an important signaling pathway, responsible for transmitting histamine signals that trigger inflammatory reactions.
10.1016/j.ceca.2011.04.004
Clinical Impact of Gastric Acid-Suppressing Medication Use on the Efficacy of Erlotinib and Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations.
Zenke Yoshitaka,Yoh Kiyotaka,Matsumoto Shingo,Umemura Shigeki,Niho Seiji,Ohmatsu Hironobu,Goto Koichi,Ohe Yuichiro
Clinical lung cancer
BACKGROUND:Gastric acid-suppressing medications (AS), namely, proton pump inhibitors and histamine-2 receptor antagonists, increase gastric pH, which may reduce the absorption of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors-erlotinib and gefitinib. PATIENTS AND METHODS:From 2008 to 2011, 130 consecutive patients with advanced non-small-cell lung cancer (NSCLC) harboring EGFR mutations were treated with either erlotinib or gefitinib at our institution. The clinical characteristics of the patients were reviewed, and the efficacy and toxicity of erlotinib and gefitinib were compared for patients receiving and not receiving AS. RESULTS:Among the 130 patients, 47 received AS (AS users group), while the remaining 83 patients did not (AS non-users group). The overall response rate (ORR) and median progression-free survival (PFS) in the subject population was 60% and 10 months, respectively. In the AS users and non-users groups, the ORR was 64% and 63% (P = .92), while the median PFS was 8.7 and 10.7 months (P = .13), respectively. No significant difference in either ORR or PFS was observed between the 2 groups. With regard to the toxicity, the frequencies of rash (83% vs. 86%; P = .60) and diarrhea (34% vs. 29%; P = .55) were similar for both groups. A multivariate analysis identified that AS use was not a significant factor for either PFS or OS. CONCLUSION:Concurrent use of AS did not affect the efficacy or toxicity of erlotinib and gefitinib in patients with advanced NSCLC harboring EGFR mutations.
10.1016/j.cllc.2016.01.006
Histamine-2 receptor antagonists and risk of lung cancer in diabetic patients – an exploratory analysis.
Hsu Chia-Lin,Chang Chia-Hsuin,Lin Jou-Wei,Wu Li-Chiu,Chuang Lee-Ming,Lai Mei-Shu
Pharmacoepidemiology and drug safety
PURPOSE:Histamine-2 receptor blockers (H2RBs) might have anti-tumorogenic effect, but the clinical effect on lung cancer occurrence was unclear. METHODS:A total of 640,173 type 2 diabetic patients were identified from the Taiwan National Health Insurance claims database in 2000. Patients were followed from cohort entry to the earliest of cancer diagnosis, death, disenrollment from the national health insurance, or 31 December 2007. For each participant, H2RB use during the follow-up period was ascertained from the outpatient pharmacy prescription database. Patients with incident squamous cell carcinoma (SCC) and adenocarcinoma were included as cases and up to four age- and sex-matched controls were selected by risk-set sampling. Conditional logistic regression models were applied to estimate the association between H2RBs and lung cancer incidence. RESULTS:A total of 1182 incident SCC and 2345 adenocarcinoma cases were identified, and 13,108 matched controls were selected. An increased risk was observed for H2RBs use <1 year with adjusted OR of 1.33 (95% confidence interval (CI): 1.22–1.44). After excluding all exposures occurring in the year before lung cancer diagnosis, H2RBs use with cumulative dosage ≥ 360 “defined daily doses” was associated with a significantly decreased risk of lung cancer (OR: 0.60; 95% CI: 0.38–0.96). When we stratified on types of lung cancer, the protective association of higher cumulative use of H2RBs seemed more evident for lung adenocarcinoma, with an adjusted OR of 0.49 (95% CI: 0.26–0.90). CONCLUSIONS:Higher cumulative use of H2RBs might be associated with a reduced risk for non-small cell lung cancer in diabetic patients.
10.1002/pds.3441
Effects of Histamine 2-receptor Antagonists and Proton Pump Inhibitors on the Pharmacokinetics of Gefitinib in Patients With Non-small-cell Lung Cancer.
Yokota Hayato,Sato Kazuhiro,Okuda Yuji,Kobayashi Hiroyuki,Takeda Masahide,Asano Mariko,Ito Hiroshi,Miura Masatomo
Clinical lung cancer
INTRODUCTION:In this study, we investigated the degree of drug interactions between gefitinib and gastric acid suppressants (ie, histamine 2-receptor antagonists [H2RAs] or proton pump inhibitors [PPIs]) with a clinical standard dose in Japanese patients with non-small-cell lung cancer. METHODS:Retrospectively, 47 patients were divided into 3 groups: gefitinib therapy with a PPI (15 patients) or an H2RA (8 patients) or gefitinib therapy alone (24 patients). On day 15 after beginning gefitinib therapy (administration at 08:00) with or without H2RA (administration twice daily at 08:00 and 18:30) or PPI (administration once daily at 08:00 or 18:30), whole blood samples were collected just prior to and at 1, 2, 4, 6, 8, 12, and 24 hours after administration. RESULTS:The total area under the observed plasma concentration-time curve (AUC) and the maximum and trough plasma concentrations of gefitinib with the PPI were significantly lower than those without the PPI. The AUC of gefitinib with PPI administration in either the morning or evening were significantly lower than those without PPI administration (P = .015 and .049, respectively); however, there were no significant differences in gefitinib AUC between patients taking PPI in the morning and evening. No significant differences were observed in gefitinib exposure among the 3 CYP2C19 genotypes. The AUC of gefitinib with H2RA tended to be lower than that without H2RA. CONCLUSION:If the plasma concentrations of gefitinib cannot be monitored, the combination of gefitinib and PPI should be avoided, and an H2RA should also be used carefully.
10.1016/j.cllc.2017.05.010
The HRH4 rs11662595 mutation is associated with histamine H receptor dysfunction and with increased epithelial-to-mesenchymal transition progress in non-small cell lung cancer.
Cai Wen-Ke,Zhang Jia-Bin,Chen Ji-Hui,Meng Jing-Ru,Ma Xue,Zhang Juan,Zhou Ya-Lin,Xu Gui-Li,He Gong-Hao
Biochimica et biophysica acta. Molecular basis of disease
We previously demonstrated that histamine H receptor (HRH4) played important roles to suppress epithelial-to-mesenchymal transition (EMT) progress in non-small cell lung cancer (NSCLC). Furthermore, recent investigations suggested that genetic variations in HRH4 gene affected HRH4 function and eventually contributed to certain HRH4-related diseases. However, the relations between polymorphisms in HRH4 gene and NSCLC as well as their underlying mechanisms remain largely uninvestigated. This study aims to investigate the genetic effect of a nonsynonymous HRH4 polymorphism (rs11662595) on HRH4 function and its association with NSCLC both basically and clinically. For basic experiments, A549 cells were transfected with either wild type or rs11662595 mutated HRH4 clone and subjected to both in vitro and in vivo experiments. We showed that rs11662595 significantly decreased the ability of HRH4 to activate Gi protein, which resulted in facilitation of EMT progress, cell proliferation, and invasion behavior in vitro. Moreover, in vivo experiments also showed that rs11662595 attenuated the anti-EMT effects of HRH4 agonist in inoculated nu/nu mice. For clinical experiments, we performed a prospective cohort study among 624 NSCLC patients and further proved that rs11662595 was responsible for the prognosis, degree of malignancy and metastasis of NSCLC. In conclusion, these findings reveal that rs11662595 is a loss-of-function polymorphism that results in dysfunction of HRH4 and attenuates the anti-EMT function of HRH4 in NSCLC, which provides a promising biomarker for prognosis and therapy of NSCLC.
10.1016/j.bbadis.2017.08.018