Leukotriene Inhibitors

 GENERAL SUMMARY:

• Leukotriene inhibitors are medications that block inflammatory substances called leukotrienes, helping to alleviate and prevent asthma symptoms and allergic reactions.

• Recent studies suggest potential benefits of leukotriene inhibitors in conditions such as cancer, obesity-related inflammation, diabetes, heart disease, and neurological aging.

ANTI-CANCER EFFECTS:

• LTRA (Cysteinyl Leukotriene Receptor Antagonists) use in asthma patients from Taiwan demonstrated a dose-dependent decrease in cancer risk across all cancers studied, warranting further study of their chemopreventive potential (2016).

• LTRA use in Korea was associated with a decreased cancer risk, especially when used in high doses and for longer durations (2022).

• In a 2017 study, arachidonate 5-lipoxygenase (Alox5) was found to be a key genetic effector of JAK2V617F in driving Polycythemia Vera (PV), while  combining 5-lipoxygenase (5-LOX) inhibitor zileuton with JAK2 inhibitor ruxolitinib demonstrated enhanced antitumor activity in PV mice (2021).

• Pharmaxis developed PXS-5505, an oral pan-LOX inhibitor initially developed for Myelofibrosis (MF) treatment, showing positive results in a phase 2 cancer trial with significant reductions in fibrosis (2022)

• Galecto's Phase 2a trial (MYLOX-1) of GB2064 for MF treatment demonstrated positive results, with a majority of patients experiencing a reduction in collagen fibrosis of the bone marrow, indicating potential disease-modifying effects (link).

• Leukotriene inhibitor exposure in U.S. veterans with asthma was associated with a reduced risk of lung cancer (2021).

• Montelukast, a leukotriene inhibitor, induces apoptosis in lung cancer cells, suggesting a potential therapeutic use (2017).

• CysLT1R antagonists demonstrated inhibition of tumor growth in a colon cancer xenograft model (2013).

• LTRAs demonstrated potential as chemoprevention candidates in colorectal cancer by reducing aberrant crypt foci formation in a nonrandomized, open-label, controlled trial (2022).

• Leukotriene signaling promotes tumor growth and metastasis, suggesting potential for pharmacological targeting in tumor metastasis treatment (2020).

METABOLIC EFFECTS:

• A 2011 review discussed the role of lipoxygenases, specifically 5-lipoxygenase and its derived products (leukotrienes), in exacerbating adipose tissue inflammation and related pathologies in obesity. Overexpression of the 5-lipoxygenase pathway and increased leukotriene production are common in excessive visceral fat depots, where they induce inflammation and promote insulin resistance.

• A 2021 study showed that montelukast, an LTRA, led to significant improvements in liver stiffness, liver enzymes, metabolic parameters, and liver fibrosis biomarkers in patients with non-alcoholic steatohepatitis (NASH).

• The 2023 study aimed to evaluate the effectiveness, tolerability, and safety of combining montelukast therapy with metformin in obese diabetic patients. After 12 weeks of treatment, the montelukast group significantly improved in all parameters compared to the placebo group. 

• The 2018 systematic review of 28 studies (26 animal studies and 2 human clinical trials) concluded that leukotriene inhibitors potentially reduced the risk of myocardial infarction, ischemic stroke, and atherosclerosis in both animal studies and human trials, suggesting a potential role in reducing CVD.

• A 2015 study suggested that leukotriene receptor inhibition may be a druggable target to restore cognitive functions in the elderly.

• A 2020 observational study using Norwegian registry data found that previous use of montelukast correlated with improved scores on cognitive or neurological functioning. 

DEEPER DIVE:

Leukotriene inhibitors are a class of medications that block the action of leukotrienes, which are inflammatory substances produced by the body in response to allergens and other triggers. Leukotrienes contribute to the symptoms of asthma and allergic rhinitis, such as airway inflammation, bronchoconstriction, mucus production, and swelling. By blocking the action of leukotrienes, these medications help to alleviate and prevent asthma symptoms and allergic reactions.

Recent research has suggested that leukotriene inhibitors may have potential benefits in other conditions, such as obesity-related inflammation, diabetes, heart disease, cancer, and neurological aging, although more studies are needed to confirm these findings. Two new leukotriene inhibitor drugs are in clinical trials against Myeloproliferative Neoplasms. The initial data points are positive.

Researchers have been investigating the role of various enzymes and inhibitors in the treatment of myeloproliferative neoplasms (MPNs) such as polycythemia vera (PV) and primary myelofibrosis (PMF). In a 2017 study, arachidonate 5-lipoxygenase (Alox5) was found to be a key genetic effector of JAK2V617F in driving PV, and its inhibition showed potential as a therapeutic target for treating MPNs. In a 2021 study, the combination of 5-lipoxygenase inhibitor zileuton and JAK2 inhibitor ruxolitinib demonstrated enhanced antitumor activity in hematopoietic progenitor cells from PV patients, providing conceptual validation for further clinical applications of this combined treatment.

In PMF, an enzyme called lysyl oxidase (LOX) has been identified as a potential novel therapeutic target. LOX plays a key role in the extracellular matrix (ECM) by facilitating the cross-linking of collagen and elastin fibers. The development of two new small molecule LOX inhibitors have shown promise in slowing PMF progression in pre-clinical studies. These inhibitors have the potential to target the dysregulation of the ECM via LOX inhibition, offering a new therapeutic approach for PMF.

Pharmaxis has developed an oral pan-LOX inhibitor called PXS-5505, which inhibits all lysyl oxidase family members. The compound has demonstrated significant reductions in fibrosis in in-vivo models of various fibrotic disorders and cancers with prominent stroma or fibrotic metastatic niches. Pharmaxis is initially developing PXS-5505 for myelofibrosis. (link, 2022, 2022)

In a phase 2 cancer trial, 15 patients were enrolled, with six completing 24 weeks of treatment. PXS-5505 was well tolerated, with no serious treatment-related adverse events. Two of the six patients experienced clinically important symptom improvement, and five of the six patients had stable or improved bone marrow fibrosis scores and platelet and/or hemoglobin scores. However, no reductions in spleen volume were observed.

Galecto, a clinical-stage biotechnology company, announced positive results from an intermediate assessment of its ongoing Phase 2a trial (MYLOX-1) of GB2064 for myelofibrosis treatment. Four out of five evaluable patients receiving GB2064 monotherapy for at least six months experienced a ≥1-grade reduction in collagen fibrosis of the bone marrow, suggesting that GB2064 could impact disease progression and be disease-modifying. (link)

A 2016 study found that cysteinyl leukotriene receptor antagonists (LTRAs) significantly decreased cancer risk in asthma patients in a dose-dependent manner. Leukotrienes, which are involved in inflammatory disorders, have been found to promote tumor growth and resistance to immunotherapy. Pharmacological targeting of leukotriene signaling in tumor metastasis is an emerging possibility.

A 2021 study showed that montelukast, an LTRA, led to significant improvements in liver stiffness, liver enzymes, metabolic parameters, and liver fibrosis biomarkers in patients with non-alcoholic steatohepatitis (NASH). Montelukast was well-tolerated and did not cause depression, suggesting potential as a promising therapeutic strategy for NASH.

A 2011 review discussed the role of lipoxygenases, specifically 5-lipoxygenase and its derived products (leukotrienes), in exacerbating adipose tissue inflammation and related pathologies in obesity. Overexpression of the 5-lipoxygenase pathway and increased leukotriene production are common in excessive visceral fat depots, where they induce inflammation and promote insulin resistance. The 5-lipoxygenase pathway also plays a significant role in inflammation in hepatic tissue and is a pathogenic factor in obesity-induced nonalcoholic fatty liver disease (NAFLD). Modulation of lipoxygenases could be a novel target for preventing adipose tissue and hepatic dysfunction related to metabolic syndrome.

The 2023 study aimed to evaluate the effectiveness, tolerability, and safety of combining montelukast therapy with metformin in obese diabetic patients. After 12 weeks of treatment, the montelukast group significantly improved in all parameters compared to the placebo group. Montelukast adjuvant therapy was found to be superior to metformin-only therapy in diabetes control and weight loss, likely due to increased insulin sensitivity and anti-inflammatory properties. The combination was safe and tolerable throughout the study.

The 2018 systematic review of 28 studies (26 animal studies and 2 human clinical trials) concluded that leukotriene receptor antagonists, such as montelukast, potentially reduced the risk of myocardial infarction, ischemic stroke, and atherosclerosis in both animal studies and human trials, suggesting a potential role in reducing some cardiovascular diseases.

The 2022 nonrandomized, open-label, controlled trial studied the effect of leukotriene receptor antagonists (LTRAs) on colorectal aberrant crypt foci (ACF) formation in humans. The trial enrolled 40 patients and found a significant decrease in ACFs in the LTRA group compared to the observation group, suggesting LTRAs as potential candidates for colorectal cancer chemoprevention.

Montelukast, an approved anti-asthmatic drug, has been shown to reduce neuroinflammation, increase hippocampal neurogenesis, and improve learning and memory in old rats by inhibiting the GPR17 receptor. This suggests that leukotriene receptor inhibition may be a druggable target to restore cognitive functions in the elderly, 2015.

The suppression of the 5-lipoxygenase (5LO) pathway, including the use of montelukast, has been considered safe in chronic conditions like asthma and could potentially benefit patients with Alzheimer's disease, non-AD amyloidoses, tauopathies, oxidation-linked nervous system disorders, and inflammation-centered disease processes, 2015.

A 2020 observational study using Norwegian registry data found that previous use of montelukast correlated with improved scores on cognitive or neurological functioning. The study suggests that montelukast may alleviate degenerative neurological changes associated with human aging and potentially postpone mental aging. The findings may help initiate clinical trials to examine the effect of montelukast on aging.

Alox5 Blockade Eradicates JAK2V617F-Induced Polycythemia Vera in Mice, 2017

Myeloproliferative neoplasms such as polycythemia vera (PV), which are associated with the JAK mutation V617F, remain incurable despite progress in the use of JAK2 inhibitors for treatment of some of these diseases. In this study, we employed mice that undergo JAK2V617F-induced PV as a tool to explore new candidate targets for therapy. Our investigations focused on the lipid metabolic enzyme arachidonate 5-lipoxygenase (Alox5), which we found to be strongly upregulated by JAK2V617F in hematopoietic cells in vitro and in vivo Notably, genetic deletion of Alox5 or its inhibition in mice with a bioactive small-molecule inhibitor was sufficient to attenuate PV development. This therapeutic effect was associated with induction of a blockade in cell-cycle progression and also with apoptosis in PV cells. Genetic loss exerted an inhibitory effect on PV-initiating cells. Similarly, Alox5 inhibition was sufficient to suppress colony formation in human JAK2V617F-expressing CD34+ cells. Mechanistic investigations showed that Alox5 inhibition reduced AKT activation and decreased β-catenin expression in JAK2V617F-expressing cells. Together, our results define Alox5 as a key genetic effector of JAK2V617F in driving PV, and they identify this enzyme as a candidate therapeutic target to treat this refractory myeloproliferative neoplasm

(minimal effect on normal leftmost stem cells; significant inhibition on middle and rightmost cancer cells)

A drug targeting 5-lipoxygenase enhances the activity of a JAK2 inhibitor in CD34 + bone marrow cells from patients with JAK2V617F-positive polycythemia vera in vitro, 2021

Janus kinase 2 (JAK2) inhibitors, the first targeted treatments for myeloproliferative neoplasms (MPNs), provide substantial benefits, including a marked reduction in splenomegaly and MPN-associated symptoms. However, these drugs rarely induce molecular remission in patients with MPNs. Zileuton, a 5-lipoxygenase (5-LO) inhibitor, has been demonstrated to selectively deplete hematopoietic stem cells (HSCs) expressing a JAK2 point mutation (JAK2V617F) in mouse models of JAK2V617F-induced polycythemia vera (PV). To determine the potential activity of 5-LO inhibitors in combination with JAK inhibitors against human PV HSCs, the present study first analyzed 5-LO expression in CD34+ bone marrow cells from patients with JAK2V617F-positive PV using western blotting and reverse transcription-quantitative PCR, and then examined the effect of zileuton combined with ruxolitinib on colony formation using a colony formation assay. Furthermore, cell cycle and apoptosis in CD34+ cells from patients with PV and healthy volunteers were determined by flow cytometry. In the present study, 5-LO expression was upregulated in CD34+ cells from patients with PV compared with in CD34+ cells from healthy volunteers. Higher levels of leukotriene B4, a product of the 5-LO signaling pathway, were detected in patients with PV compared with in healthy volunteers. Zileuton treatment suppressed the colony formation of CD34+ cells from patients with PV in a dose-dependent manner. Furthermore, zileuton and ruxolitinib exerted their anticancer effects by suppressing hematopoietic colony formation, inducing apoptosis and arresting the cell cycle of human CD34+ cells from patients with PV. The combination of these two drugs exerted a more beneficial effect than either agent alone. Based on these data, zileuton enhanced the antitumor activity of low-dose ruxolitinib in hematopoietic progenitor cells from patients with PV, providing conceptual validation for further clinical applications of combination treatment with ruxolitinib and zileuton for patients with PV.

5-LO expression is upregulated in numerous different types of cancer, including pancreatic, breast, prostate, esophageal and colon cancer (29–33). The products of 5-LO, such as 5-hydroxyeicosatetraenoic acid (5-HETE) and LTs, are able to promote cell proliferation, suppress apoptosis, promote angiogenesis and enhance tumor cell invasion (34–36). According to previous studies, epidermal growth factors and neurotensin are involved in the 5-LO-mediated tumor progression in individuals with prostate cancer (37,38). A study of patients with colorectal cancer revealed that 5-HETE stimulates angiogenesis by inducing the expression of VEGF (39,40). Furthermore, increased activities of 5-LO and matrix metalloproteinases are associated with extracellular matrix stiffness (41) and enhance the invasiveness of cancer cells (42,43). The enzyme 5-LO is involved in the development of not only solid malignancies but also certain forms of leukemia (44,45). Recently, the 5-LO gene was shown to be a critical regulator for mouse leukemic stem cells (LSCs) in BCR-ABL-induced chronic myeloid leukemia (CML), and the combination of zileuton and imatinib extends the survival time of mice with CML (46). This finding motivated an initial clinical trial combining zileuton with imatinib as a treatment for CML (clinicaltrials.com). Zileuton has been revealed to selectively deplete JAK2V617F-expressing HSCs, thereby preventing PV development in mice (14). The molecular mechanism of 5-LO in PV is associated with the β-catenin signaling pathway, which is required for the maintenance of both HSCs (47) and LSCs in individuals with CML (48–50).

Lysyl oxidase inhibition in primary myelofibrosis: A renewed strategy, 2021

Primary myelofibrosis (PMF) is a type of myeloproliferative neoplasm (MPN) that portends a poor prognosis and has limited options for treatment. PMF is often driven by clonal mutations in one of three genes that regulate the JAK-STAT signaling pathway, leading to hyperactivation of this signaling pathway and over-proliferation of megakaryocytes (MKs) and their precursors. PMF presents with debilitating symptoms such as splenomegaly and weight loss. The few available treatments for PMF include a JAK2 inhibitor, ruxolitinib, which causes side effects and is not always effective. The extracellular matrix (ECM) and bone marrow (BM) microenvironment may play an important role in the pathogenesis of PMF. Lysyl oxidase (LOX), an enzyme that plays a key role in the ECM by facilitating the cross-linking of collagen and elastin fibers, has been shown to be upregulated in MKs of PMF mice and in PMF patients, suggesting its role in the progression of BM fibrosis. Recently, LOX has been identified as a potential novel therapeutic target for PMF and the development of new small molecule LOX inhibitors, PXS-LOX_1 and PXS-LOX_2, has shown some promise in slowing the progression of PMF in pre-clinical studies. Given that these inhibitors displayed an ability to target the dysregulation of the ECM via LOX inhibition, they show promise as therapeutic agents for an underappreciated aspect of PMF.

Beth K.

Hello Friends, 

I am very excited to share an update regarding my recent JAK2 results— it is below .5% ! My first JAK2 test result in July 2016 was 69.9%. I was on Pegasys for 10 months, and it dropped steadily. I added in Singulair at 5th month of treatment after reading about Dr. Li’s Research. I went into molecular remission in May 2017, JAK2 was at 6.07%, and was taken off of Pegasys, as my platelets dropped to 77. I have been off Pegasys for 13 months, only on Singulair and a baby aspirin, and during this time my JAK2 continued to drop to current result of below .5%. I have had a wonderful success with Pegasys, with very little side effects. I am also vegan, and take Singulair as mentioned above. (My platelets hover around 130.)

Oral pan-LOX Inhibitor (PXS-5505) (link)

Pharmaxis has developed an oral drug inhibiting all lysyl oxidase family members. The compound has shown significant reductions in fibrosis in in-vivo models of myelofibrosis, myelodysplastic syndrome, pancreatic cancer, kidney fibrosis and lung fibrosis,. This all-encompassing LOX inhibitor is well positioned for the treatment of severe fibrosis as well as cancer with prominent stroma (connective tissue) or fibrotic metastatic niches. Pharmaxis is initially developing the compound for myelofibrosis.

PXS-5505: Pharmaxis positive interim data from myelofibrosis phase 2 cancer trial, 2022

A total of 15 patients have been enrolled in the cohort expansion phase of the study with 6 patients having completed 24 weeks of treatment (6 months). Four patients have dropped out of the study due to a lack of clinical response. 

• PXS-5505 has been well tolerated with no serious treatment related adverse events reported. 

• 2/6 patients had clinically important improvement in symptoms. 

• 5/6 patients had either stable or improved bone marrow fibrosis scores of ≥1 grade. 

• 5/6 have stable or improved platelet and/or haemoglobin scores. 

• No reductions were seen in spleen volume. 

“This is encouraging given the poor prognoses seen after ruxolitinib discontinuation with a median overall survival of only 11-14 months, typical of this study population. These results support further clinical investigation of PXS-5505 in myelofibrosis.”

Phase 1/2a study to evaluate safety, pharmacokinetic and pharmacodynamic dose escalation and expansion study of pxs-5505 in patients with primary, postpolycythemia vera or post-essential thrombocythemia myelofibrosis, 2022

Dr Gabriela Hobbs (Massachusetts General Hospital) on the myelofibrosis landscape and MF-101 can be seen here.

GB-2064 by Galecto (link)

Galecto, Inc. (NASDAQ: GLTO), a clinical stage biotechnology company focused on the development of novel treatments for fibrosis and cancer, today announced positive results from a planned intermediate assessment of its ongoing Phase 2a trial of GB2064 for the treatment of myelofibrosis (“MYLOX-1 trial”, NCT04679870). Fibrosis is a key disease mechanism of myelofibrosis that destroys the bone marrow function. Reducing fibrosis is required to slow the progression of the disease. Four out of five evaluable myelofibrosis patients who received GB2064 monotherapy for at least six months in the MYLOX-1 trial experienced a ≥ 1-grade reduction in collagen fibrosis of the bone marrow, an improvement suggesting that GB2064 could impact the progression of the disease and be disease modifying.

Patient Note

Just frustrated that none of the drugs that actually have reversed fibrosis are available to me. two are Lysyl Oxidase Inhibitors. PXS-5505 by Pharmaxis and GB-2064 by Galecto. Both in phase 2 trials. Dr. Mesa advised me that none of the MF trial drugs were suitable. He says that I’m still PV with some scarring(grade 2) not post PV/MF-2.

Reversing fibrosis – the ploidy connection, 2011

5 lox vs  pan lox inhibitor

Lox inhibitors and pan-Lox inhibitors are types of drugs that target lipoxygenases (Lox), a family of enzymes involved in the metabolism of arachidonic acid, which is a key component in the production of inflammatory mediators called leukotrienes. Lox inhibitors are designed to specifically target one or more isoforms of the lipoxygenase enzyme, while pan-Lox inhibitors target multiple isoforms at once. The distinction between the two lies in their specificity and breadth of action.

1. Specificity: 5-Lox inhibitors are designed to selectively target the 5-lipoxygenase (5-Lox) enzyme isoform. This isoform is primarily involved in the production of leukotrienes, which contribute to inflammation and various inflammatory diseases, such as asthma, arthritis, and atherosclerosis. By inhibiting this particular isoform, 5-Lox inhibitors can help reduce inflammation and alleviate symptoms associated with these conditions.

Pan-Lox inhibitors, on the other hand, target multiple isoforms of the lipoxygenase enzyme family, rather than focusing on a specific isoform like 5-Lox inhibitors. By inhibiting several isoforms, pan-Lox inhibitors can exert broader anti-inflammatory effects, which might be beneficial in treating a wider range of inflammatory diseases or conditions.

2. Therapeutic applications: Due to their specificity, 5-Lox inhibitors are typically used to treat inflammatory conditions where the 5-lipoxygenase enzyme plays a significant role, such as asthma, arthritis, and atherosclerosis. In contrast, pan-Lox inhibitors may be utilized in a broader range of inflammatory conditions, potentially including those where multiple lipoxygenase isoforms contribute to disease progression.

3. Potential side effects: Since pan-Lox inhibitors target multiple isoforms, they may have a higher risk of causing unintended side effects compared to more targeted 5-Lox inhibitors. However, the specific side effect profile for each drug depends on its chemical structure and other factors.

What are Leukotriene receptor antagonists (LTRAs)?

Leukotriene receptor antagonists (LTRAs) are a class of drugs that work by blocking the action of leukotrienes, which are inflammatory molecules involved in the pathophysiology of asthma and allergic rhinitis. Some of the commonly prescribed LTRAs include:

Montelukast (brand name: Singulair): Montelukast is a widely used LTRA for the treatment of asthma, exercise-induced bronchoconstriction, and allergic rhinitis. It selectively blocks the cysteinyl leukotriene receptor type 1 (CysLT1) and helps to reduce bronchoconstriction, mucus production, and inflammation in the airways.

Zafirlukast (brand name: Accolate): Zafirlukast is another LTRA used in the management of asthma. Like montelukast, it also selectively blocks the CysLT1 receptor and helps to alleviate asthma symptoms by reducing airway inflammation and constriction.

Pranlukast (brand name: Onon): Pranlukast is an LTRA available in some countries, primarily in Asia, for the treatment of asthma and allergic rhinitis. It also works by blocking the CysLT1 receptor and has a similar mechanism of action as montelukast and zafirlukast.

Cysteinyl Leukotriene Receptor Antagonists Decrease Cancer Risk in Asthma Patients, 2016

Previous in vitro and in vivo studies have demonstrated the potential of using cysteinyl leukotriene receptor antagonists (LTRAs) for chemoprevention, but this has not been investigated in any clinical setting. We therefore investigated the chemopreventive effect of LTRAs in a nationwide population-based study. From the Taiwan National Health Insurance Research Database, we enrolled adults with newly-diagnosed asthma between 2001 and 2011. Among these patients, each LTRA user was matched with five randomly-selected LTRA non-users by sex, age, asthma diagnostic year and modified Charlson Comorbidity Index score. We considered the development of cancer as the outcome. Totally, 4185 LTRA users and 20925 LTRA non-users were identified. LTRA users had a significantly lower cancer incidence rate than LTRA non-users did. Multivariable Cox regression analyses adjusting for baseline characteristics and comorbidities showed LTRA use was an independent protecting factor (hazard ratio = 0.31 [95% CI: 0.24–0.39]), and cancer risk decreased progressively with higher cumulative dose of LTRAs. In conclusion, this study revealed that the LTRA use decreased cancer risk in a dose-dependent manner in asthma patients. The chemopreventive effect of LTRAs deserves further study.

Cysteinyl Leukotriene Receptor Antagonists Associated With a Decreased Incidence of Cancer: A Retrospective Cohort Study, 2022 [From Korea]

Aim: Cysteinyl leukotrienes receptor antagonists (LTRAs) are promising chemoprevention options to target cysteinyl leukotriene signaling in cancer. However, only a number of randomized clinical trials (RCTs) or observational studies have been conducted to date; thus, the effect of LTRAs on patients is yet to be elucidated. Using insurance claim data, we aimed to evaluate whether LTRAs have cancer preventive effects by observing patients who took LTRAs.

Method: Patients diagnosed with asthma, allergic rhinitis, chronic cough, and have no history of cancer were followed-up from 2005 to 2017. Cox proportional hazard regression analysis was conducted to estimate the hazard ratios (HRs) for cancer risk of LTRA users.

Result: We followed-up (median: 5.6 years) 188,906 matched patients (94,453 LTRA users and 94,453 non-users). LTRA use was associated with a decreased risk of cancer (adjusted HR [aHR] = 0.85, 95% confidence interval [CI] = 0.83–0.87). The cancer risk showed a tendency to decrease rapidly when LTRAs were used in high dose (aHR = 0.56, 95% CI = 0.40–0.79) or for longer durations of more than 3 years (aHR = 0.68, 95% CI = 0.60–0.76) and 5 years (aHR = 0.33, 95% CI = 0.26–0.42). The greater preventive effects of LTRAs were also observed in patients with specific risk factors related to sex, age, smoking, and the presence of comorbidities.

Conclusion: In this study, we found that LTRA use was associated with a decreased risk of cancer. The high dose and long duration of the use of LTRAs correlated with a lower cancer risk. Since LTRAs are not yet used for the prevention or treatment of cancer, our findings could be used for developing a new chemo-regimen or designing feasible RCTs.

Leukotriene inhibition and the risk of lung cancer among U.S. veterans with asthma, 2021

Leukotriene inhibition, in vitro and in vivo, is found to suppress tumor growth across a variety of cancer cells. A mouse model of lung cancer revealed that the leukotriene inhibitor montelukast induced lung cancer cell death. Based on the preclinical data we hypothesize that exposure to a leukotriene inhibitor is associated with a lower risk of lung cancer. We conducted a national retrospective cohort study among U.S. Veterans with asthma to explore the relationship between leukotriene inhibition and incident lung cancer. We utilize a variety of statistical techniques, including cox proportional hazards models, propensity score matching and falsification testing to examine the association. A total of 558,466 patients met study criteria consisting of 23,730 patients with leukotriene exposure and 534,736 patients with no leukotriene medication use. Leukotriene inhibitor exposure reduced the risk of lung cancer by 17% (HR = 0.830; 95% CI = (0.757-0.911)) in the unmatched and 22.2% in the matched analysis (HR = 0.778 95% CI = (0.688-0.88)). Falsification testing with appendicitis and rotator cuff injury end points, suggest no evidence of selection bias. However, because treatment was not randomized, residual confounding cannot be ruled out. The pre-clinical data on leukotriene inhibition and lung cancer combined with our database analysis provide intriguing evidence warranting further research into the relationship between leukotrienes and lung cancer.

Leukotrienes: Inhibitors & Natural Ways to Block Them (selfhacked)

Lipoxygenase (LOX) Pathway: A Promising Target to Combat Cancer, 2021

Leukotrienes are one of the major eicosanoid lipid mediators produced due to an oxidative transformation of arachidonic acid. Subsequently, they get converted into various cellular signaling hormones by a series of enzymes of myeloid origin to mediate or debilitate inflammation. Interestingly, the available literature demonstrates the pivotal role of eicosanoids in neurodegenerative, obesity, diabetes, cardiovascular diseases, and cancers as well. The aberrant metabolism of arachidonic acid by the LOX pathway is a common feature of epithelial-derived malignancies and suggests the contributory role of dietary fats in carcinogenesis. The enzymes and receptors of the LOX pathway play a significant role in cell proliferation, differentiation and regulation of apoptosis through multiple signaling pathways and have been reported to be involved in various cancers, including prostate, colon, lung and pancreatic cancers. So far, leukotriene receptor antagonists and 5-LOX inhibitors have reached up to the clinical trials for treating various diseases. Keeping its various roles in cancer, the review highlights the components of the leukotriene synthesizing machinery, emerging opportunities for pharmacological intervention, and the probability of considering lipoxygenases and leukotriene receptors as good candidates for clinical chemoprevention studies.

Montelukast Induces Apoptosis-Inducing Factor-Mediated Cell Death of Lung Cancer Cells, 2017

CysLT1R Antagonists Inhibit Tumor Growth in a Xenograft Model of Colon Cancer, 2013

Leukotrienes in Tumor-Associated Inflammation, 2020

Leukotrienes are biologically active eicosanoid lipid mediators that originate from oxidative metabolism of arachidonic acid. Biosynthesis of leukotrienes involves a set of soluble and membrane-bound enzymes that constitute a machinery complex primarily expressed by cells of myeloid origin. Leukotrienes and their synthetic enzymes are critical immune modulators for leukocyte migration. Increased concentrations of leukotrienes are implicated in a number of inflammatory disorders. More recent work indicates that leukotrienes may also interact with a variety of tissue cells, contributing to the low-grade inflammation of cardiovascular, neurodegenerative, and metabolic conditions, as well as that of cancer. Leukotriene signaling contributes to the active tumor microenvironment, promoting tumor growth and resistance to immunotherapy. This review summarizes recent insights into the intricate roles of leukotrienes in promoting tumor growth and metastasis through shaping the tumor microenvironment. The emerging possibilities for pharmacological targeting of leukotriene signaling in tumor metastasis are considered.

Leukotriene Receptor Antagonist Therapy for the Chemoprevention of Human Rectal Aberrant Crypt Foci: Nonrandomized, Open-Label, Controlled Trial, 2022

From November 2017 to March 2020, 40 patients were enrolled. The first 30 were assigned to the LTRA group, and the remaining 10 were assigned to the observation group. In the LTRA group, the mean change in the number of ACFs per patient at 8 weeks from baseline was −2.4 ± 2.2, while the mean change in the observation group was 0.4 ± 2.3 (P = 0.002). There were no severe adverse events.

This is the first study to explore the effect of LTRAs against colorectal ACF formation in humans. LTRAs are potential candidates for chemoprevention in colorectal cancer.

Possibility of the Strategic Treatment for Various Tumors using the Leukotriene Receptor Antagonist, link

Although this is a closed trial, we have already administered the leukotriene receptor antagonist to several terminal patients, who were diagnosed as being unlikely to show any improvement, with pancreatic cancer and gastric cancer, even if conventional treatment was offered. These patients have all showed remarkable results in terms of treatment and we are currently preparing a clinical trial. As a future therapy for tumors, combination therapy with leukotriene receptor antagonists alone or other drugs is expected. We also hope that preventive medicine will be developed that prevents malignant transformation of benign tumors.

Overexpression of a cysteinyl leukotriene receptor, CysLT1R, has been shown in colorectal cancer, prostate cancer, renal cell carcinoma, transitional cell carcinoma and testicular cancer, and montelukast induces apoptosis of these cancer cells.

The leukotriene receptor antagonist montelukast in the treatment of non-alcoholic steatohepatitis: A proof-of-concept, randomized, double-blind, placebo-controlled trial, 2021

Non-alcoholic fatty liver disease (NAFLD) is associated with fat accumulation in the liver which can progress into non-alcoholic steatohepatitis (NASH). There is no specific treatment strategy for NASH. In this context, this study aimed at evaluating the efficacy and safety of montelukast in the treatment of patients with NASH. In this randomized double-blind placebo-controlled study, 52 overweight/obese patients with NASH were randomized into group 1 (n = 26) which received montelukast 10 mg tablets once daily and group 2 (n = 26) which received placebo tablets once daily for 12 weeks. The fibro-scan was used to assess liver stiffness as a primary outcome at baseline and 12 weeks post-treatment. Furthermore, patients were assessed for biochemical analysis of liver aminotransferases, metabolic parameters, TNF-α, 8-hydroxy-2'-deoxyguanosine (8-OHdG), liver fibrosis biomarkers including hyaluronic acid (HA) and transforming growth factor beta-1 (TGF-β1). Beck depression inventory questionnaire was used to report depressive symptoms. Data were statistically analyzed by paired and unpaired student's t-test, and Chi-square test. A total number of 44 patients completed the study. The two groups were statistically similar at baseline. After treatment and as compared to baseline data and placebo, montelukast showed a statistically significant improvement in liver stiffness, liver enzymes, metabolic parameters (except LDL-C), TNF-α, 8-OHdG, and liver fibrosis biomarkers (HA and TGF-β1). Furthermore, montelukast was well tolerated and didn't provoke depression. In this proof-of-concept study, treatment with montelukast may represent a promising therapeutic strategy for patients with non-alcoholic steatohepatitis secondary to its efficacy and safety. 

The liver plays an important role in both synthesis and metabolism of leukotrienes (LTs). Leukotriene A4 (LTA4) is synthesized in kupffer cells which are the only liver cell type gifted with active 5-lipoxygenase (5-LO) pathway. LTA4 is taken up by hepatocytes which can’t synthesize denovo CysLTs but can conjugate LTA4 with glutathione to produce leukotriene C4 (LTC4) (Shimada et al., 1998). Moreover, inflammatory conditions are associated with increased CysLTs levels due to decreased leukotrienes excretion (Okunishi and Peters-Golden, 2011). Several studies showed that, CysLTs are involved in the pathogenesis of bile duct obstruction, hepato-renal syndrome, metabolic disorder, and other pathological conditions (Filgueiras et al., 2015; Martínez-Clemente et al., 2011). Furthermore, experimental data indicate that, CysLTs production is increased in fatty liver disease, abdominal obesity, obstructive jaundice, metabolic and hepatic disorders in fructose-induced metabolic syndrome (B¨ ack et al., 2014; Ibrahim et al., 2014; Kuru et al., 2015; Martínez-Clemente et al., 2011). 

It has been demonstrated that, 5-lipoxygenase/leukotriene plays a role in obesity, insulin resistance and fatty liver disease (Martínez-Clemente et al., 2011). Leukotriene produced by 5-lipoxygenase pathway seems important in inflammation and chemotaxis. Therefore, enhanced expression of 5-lipoxygenase with subsequent increased leukotriene production could result in activation of nuclear factor-κB (NF-κB) which in turn can promote secretion of pro-inflammatory and insulin resistance mediators such as TNF-α. Oxidative stress stimulates liver X receptors, which release inflammatory mediators including TNF-α (Shoelson, 2006). 

Montelukast is a CysLT1 receptor antagonist that blocks the proinflammatory action of leukotriene D4 (LTD4). Montelukast is approved for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies. Montelukast inhibits neutrophil infiltration, balances oxidant-antioxidant status, fights oxidative stress and regulates the generation of inflammatory mediators (Dilek et al., 2015; Said and Bosland, 2017). Moreover, montelukast ameliorates insulin resistance which plays a critical role in the pathogenesis of NAFLD (Martínez-Clemente et al., 2011). Furthermore, it has been reported that montelukast protects against acetaminophen induced hepatotoxicity in a rat model (Weiskirchen, 2019). 

Therefore, the above mentioned data encouraged us to run the current study which aimed at examining the efficacy and safety of montelukast as a possible potential therapy for patients with NASH through evaluating its effect on liver stiffness, serum levels of liver fibrosis biomarkers (hyaluronic acid (HA) and transforming growth factor beta1 (TGF-β1), insulin resistance, metabolic and inflammatory parameters.

The 5-lipoxygenase/leukotriene pathway in obesity, insulin resistance, and fatty liver disease, 2011

Purpose of review: Obesity is a major risk factor for metabolic syndrome-related comorbidities such as insulin resistance, type-II diabetes, and nonalcoholic fatty liver disease (NAFLD). A wealth of evidence indicates that the associated pathologies of the metabolic syndrome are aggravated by the presence of a chronic state of 'low-grade' inflammation in the adipose tissue. This article discusses recent data implicating lipoxygenases and especially 5-lipoxygenase and its derived products, the leukotrienes, in mounting adipose tissue inflammation and related pathologies in obesity.

Recent findings: Overexpression of selected members of the 5-lipoxygenase pathway and increased leukotriene production are common findings in excessive visceral fat depots. In these conditions, 5-lipoxygenase products exert potent proinflammatory actions including induction of nuclear factor-κB and secretion of proinflammatory and insulin resistant adipokines (i.e., monocyte chemotactic protein-1, tumor necrosis factor-α, macrophage inflammatory protein-1γ, and interleukin-6) by adipose tissue. The 5-lipoxygenase pathway also plays a major role in mounting inflammation in hepatic tissue and has emerged as a pathogenic factor in obesity-induced NAFLD. Similar role in NAFLD has been proposed for the 12/15-lipoxygenase pathway.

Summary: Modulation of lipoxygenases represents a novel target in the prevention of adipose tissue and hepatic dysfunction related to the metabolic syndrome.

Montelukast as a potential hepatoprotective drug: montelukast attenuates acetaminophen-induced liver injury in mice, 2019

Commentary: Montelukast Prevents Mice Against Acetaminophen-Induced Liver Injury, 2019

Evaluating the safety and efficacy of the leukotriene receptor antagonist montelukast as adjuvant therapy in obese patients with type 2 diabetes mellitus: A double-blind, randomized, placebo-controlled trial, 2023

Aim: This study aimed to evaluate the effectiveness, tolerability, and safety of combining montelukast therapy with metformin in obese diabetic patients.

Methods: One hundred obese diabetic adult patients were recruited and randomized into two equal groups. Group 1 received placebo plus metformin 2 g/d, and Group 2 received 2 g/d metformin plus 10 mg/d montelukast. Demographic, anthropometric measurements (e.g., body weight, body mass index [BMI], and visceral adiposity index), lipid profile, diabetes control measures (fasting blood glucose, glycated hemoglobin [HbA1c], and homeostatic model assessment for insulin resistance [HOMA-IR]), adiponectin, and inflammatory markers (e.g., TNF-α, IL-6, and leukotriene B4) were assessed and reported for each group at baseline and after 12 weeks of treatment.

Results: Both interventions significantly reduced all the measured parameters, except for adiponectin and HDL-C, levels of which increased compared to baseline data (p < 0.001). The montelukast group significantly improved in all parameters compared to the placebo group (ANCOVA test p < 0.001). The percentage changes in BMI, HbA1c, HOMA-IR, and inflammatory markers were 5%, 9%, 41%, and 5%–30%, respectively, in the placebo group compared to 8%, 16%, 58%, and 50%–70%, respectively, in the montelukast group.

Conclusion: Montelukast adjuvant therapy was superior to metformin-only therapy in diabetes control and weight loss, most likely due to its increased insulin sensitivity and anti-inflammatory properties. The combination was tolerable and safe throughout the study duration.

Potential role of leukotriene receptor antagonists in reducing cardiovascular and cerbrovascular risk: A systematic review of human clinical trials and in vivo animal studies, 2018

A total of 28 studies were included, of which 26 were conducted in animals, and 2 in humans.

Conclusions

All animal studies reported that using a leukotriene receptor antagonist brings to a reduction of either myocardial infarction, ischemic stroke, or atherosclerosis risk. Similar results were obtained from two clinical trials on humans, suggesting a potential role of montelukast in reducing some cardiovascular diseases.

Montelukast, cysteinyl leukotriene receptor 1 antagonist, inhibits cardiac fibrosis by activating APJ, 2022

Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug, 2015

A 6-week treatment of young (4 months) and old (20 months) rats with montelukast, a marketed anti-asthmatic drug antagonizing leukotriene receptors, reduces neuroinflammation, elevates hippocampal neurogenesis and improves learning and memory in old animals. By using gene knockdown and knockout approaches, we demonstrate that the effect is mediated through inhibition of the GPR17 receptor. This work illustrates that inhibition of leukotriene receptor signalling might represent a safe and druggable target to restore cognitive functions in old individuals and paves the way for future clinical translation of leukotriene receptor inhibition for the treatment of dementias.

The 5-lipoxygenase pathway: oxidative and inflammatory contributions to the Alzheimer’s disease phenotype, 2015

5LO pathway suppression has the added benefit of being safe in other chronic conditions such as asthma (i.e., Zileuton, Monteleukast). Beyond AD, 5LO pathway targeting may also be useful in other dementias and related conditions including: non-AD amyloidoses (i.e., cerebral amyloid angiopathy), tauopathies (e.g., frontotemporal dementia, chronic traumatic encephalopathy, progressive supranuclear palsy), oxidation-linked nervous system disorders (i.e., amyotrophic lateral sclerosis) and inflammation-centered disease processes (i.e., multiple sclerosis).

A possible effect of montelukast on neurological aging examined by the use of register data, 2020

Background The leukotriene receptor antagonist montelukast has been shown to rejuvenate aged brains in rats; however, data on humans are still scarce. Objective To investigate if montelukast may alleviate degenerative neurological changes using a register data. Setting Norwegian registry data analyses. Method The present observational study was based on data from the Norwegian Prescription Database and the Tromsø Study. The former has information regarding the use of prescription medicine; the latter includes tests for brain function such as subjective memory and finger-tapping. Multivariate linear regression analyses were performed to see how the use of various medications correlated with the test results, correcting for likely confounders. Main outcome measure Results on seven different tests considered relevant for neurological health were used as outcome. Results Previous use of montelukast correlated with improved scores on cognitive or neurological functioning (F = 2.20, p = 0.03 in a multivariate test). A range of other medications were tested with the same algorithm, including drugs acting on the immune system, but none of them correlated with (overall) significantly improved test results. Conclusion The present data suggest that montelukast may alleviate degenerative neurological changes associated with human aging.

• The data suggest that montelukast may postpone mental aging.

• The dosage used for asthma may not be optimal for possible effects on the brain.

• The data should help initiate a clinical trial to examine the effect of montelukast on aging.

Comparative study evaluating antihistamine versus leukotriene receptor antagonist as adjuvant therapy for rheumatoid arthritis, 2021

Purpose

Investigating the efficacy and safety of rupatadine (RUP) versus montelukast (MON) as adjuvant therapy for patients with rheumatoid arthritis (RA).

Methods

From December 2018 to December 2019, 75 patients with active RA were enrolled in this randomized double-blind placebo-controlled study. The patients were randomized into three groups (n = 25 in each group); methotrexate (MTX) group which received MTX 15–25 mg/week plus placebo tablet once daily; MTX/RUP group which received MTX plus RUP 10 mg once daily; and MTX/MON group which received MTX plus MON 10 mg once daily. The treatment duration was 3 months. At baseline and 3 months after treatment, blood samples were collected for the biochemical analysis of high-sensitivity C-reactive protein (hs-CRP), interleukins 8 and 17 (IL-8, IL-17), E-selectin, and clusterin (CLU) levels. Clinical and functional assessments using Disease Activity Score-CRP (DAS28-CRP) and Multidimensional Health Assessment Questionnaire (MDHAQ) were performed.

Results

Both RUP and MON produced clinical and functional improvements which were translated by significant improvements in DAS28-CRP score and MDHAQ. Rupatadine significantly reduced all measured parameters (P < 0.05) except for IL-17 and CLU. Montelukast significantly decreased all measured variables (P < 0.05) except for E-selectin. Interleukin-8 was positively correlated with IL-17 and CLU, while hs-CRP was positively correlated with E-selectin and body mass index (BMI). Both drugs were well tolerated; somnolence was the common side effect for RUP. No neuropsychiatric events were reported with MON.

Conclusion

Rupatadine or montelukast may serve as a potential adjuvant therapy for patients with rheumatoid arthritis secondary to the preliminary evidence of efficacy and safety.

The Effect of Montelukast and Low-Dose Theophylline on Cardiovascular Disease Risk Factors in Asthmatics, 2007

Background

Recent studies have implicated the 5-lipoxygenase/leukotriene (LT) pathway in cardiovascular disease (CVD), which may have important implications for asthmatics because several drugs that target this pathway are currently used to treat asthma. We sought to determine whether montelukast, a cysteinyl LT antagonist, and low-dose theophylline affected serum inflammatory and lipid CVD risk factors in a recently completed clinical trial in asthmatic patients.

Methods

Patients were randomized to receive either montelukast (10 mg/d), theophylline (300 mg/d), or placebo. A baseline run-in period of 7 to 14 days was followed by treatment for 6 months. Serum levels of C-reactive protein (CRP), interleukin-6, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density cholesterol (HDL-C) were measured 1 month and 6 months after treatment.

Results

Patients with moderate-to-severe asthma receiving montelukast (n = 60) had significantly lower serum CRP compared to placebo (n = 73) after 1 month (1.7 mg/L vs 3.2 mg/L, respectively; p < 0.006) and 6 months of treatment (2.3 mg/L vs 3.5 mg/L, respectively; p < 0.04). At both time points, serum levels of all lipids were also significantly lower in the montelukast and theophylline groups compared to placebo, but these effects were primarily observed in individuals who were also receiving inhaled corticosteroids as monotherapy for asthma.

Conclusions

Asthmatic patients receiving montelukast and, to some extent, low-dose theophylline have lower levels of CVD-associated inflammatory biomarkers and lipid levels. These observations suggest these asthma medications may have some beneficial value in asthmatics with respect to CVD risk, although the effects on HDL-C levels should also be taken into consideration.

NDGA is a cell-permeable antioxidant and a selective lipoxygenase (LOX) inhibitor (IC₅₀ = 200 nM, 30 µM, and 30 µM for 5-LOX, 12-LOX, and 15-LOX, respectively), link.