- Cysteinyl Leukotriene Receptor Antagonists Induce Apoptosis and Inhibit Proliferation of Human Glioblastoma Cells by Down-regulating B-cell Lymphoma 2 and Inducing Cell Cycle Arrest. [Journal Article]
- CJCan J Physiol Pharmacol 2018 May 04
- Glioblastoma is the most aggressive type of brain cancer with the highest proliferation, invasion and migration. Montelukast and zafirlukast, two widely used leukotriene receptor antagonists (LTRAs) ...
Glioblastoma is the most aggressive type of brain cancer with the highest proliferation, invasion and migration. Montelukast and zafirlukast, two widely used leukotriene receptor antagonists (LTRAs) for asthma treatment, inhibited invasion and migration of glioblastoma cell lines. Montelukast induces apoptosis and inhibites cell proliferation of various cancer cells. Herein, apoptotic and antiproliferative effects of montelukast and zafirlukast were investigated in two glioblastoma cell lines, A172 and U-87 MG. Both LTRAs induced apoptosis and inhibited cell proliferation of glioblastoma cells in a concentration-dependent manner. Montelukast was more cytotoxic and induced higher levels of apoptosis than zafirlukast in A172 cells, but not in U-87 MG cells. Both drugs decreased expression of B-cell lymphoma 2 (Bcl-2) protein without affecting Bcl-2-associated X (Bax) levels. LTRAs also reduced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). In contrast, zafirlukast showed a greater antiproliferative effect than montelukast and induced G0/G1 cell cycle arrest by upregulating p53 and p21 expression. These results suggested that therapeutic potential of LTRAs in glioblastoma.
- Montelukast inhibits hypoxia inducible factor-1α translation in prostate cancer cells. [Journal Article]
- CBCancer Biol Ther 2018 Apr 30; :1-7
- Through regulating the expression of hundreds of genes, hypoxia-inducible factor -1(HIF-1) plays a critical role in hypoxic adaption of cancer cells and is considered as a target for cancer therapy. ...
Through regulating the expression of hundreds of genes, hypoxia-inducible factor -1(HIF-1) plays a critical role in hypoxic adaption of cancer cells and is considered as a target for cancer therapy. Here we show that montelukast, a clinical leukotriene receptor antagonist for the treatment of asthma, inhibits hypoxia or CoCl2-induced HIF-1α activation and reduces its protein expression in prostate cancer cells. However, the other two leukotriene receptor antagonists, pranlukast and zafirlukast, cannot decrease HIF-1α protein, which indicates that montelukast-induced downregulation of HIF-1α is not mediated by leukotriene receptor. Neither proteasome inhibitor MG132 nor the lysosomal inhibitor chloroquine (CQ) can block montelukast-induced downregulation of HIF-1α protein. Interestingly, GSK2606414, a PKR-like endoplasmic reticulum kinase (PERK) inhibitor, abrogates montelukast-induced downregulation of HIF-1α under hypoxic conditions. However, montelukast increases phosphorylation of eIF-2α at Ser51. Moreover, montelukast inhibits the proliferation of prostate cancer cells, which can be reversed by overexpression of HIF-1α protein. In conclusion, we identify montelukast may be used as a novel agent for the treatment of prostate cancer by decreasing HIF-1α protein translation.
- Zafirlukast and vincamine ameliorate tamoxifen-induced oxidative stress and inflammation: Role of the JNK/ERK pathway. [Journal Article]
- LSLife Sci 2018 Jun 01; 202:78-88
- CONCLUSIONS: Zafirlukast and vincamine may be regarded as potential therapeutic strategies with antioxidant and anti-inflammatory activities against tamoxifen-induced oxidative damage in rat liver.
- Leukotriene Receptor Antagonists Inhibit Mitogenic Activity in Triple Negative Breast Cancer Cells [Journal Article]
- APAsian Pac J Cancer Prev 2018 Mar 27; 19(3):833-837
- Despite a discovery of hormonal pathways regulating breast cancer, a definitive cure for the disease requires furtheridentification of alternative targets that provide a hormone-independent support. ...
Despite a discovery of hormonal pathways regulating breast cancer, a definitive cure for the disease requires furtheridentification of alternative targets that provide a hormone-independent support. Apart from their role in inflammatory diseases, cysteinyl leukotriene (CysLT) receptor antagonists (LTRAs) decrease the risk of lung cancer in asthma patients and inhibit tumor progression in several malignancies. In the present study, we evaluate the effects of two chemically different, clinically relevant LTRAs (montelukast and zafirlukast) in a triple negative breast cancer cell line, MDAMB- 231. We found that these two LTRAs reduced breast cancer cell viability in a dose-dependent manner with the 50% inhibitory concentration (IC50) between 5-10 μM. Although both LTRAs have several pharmacological properties in common, we noticed that montelukast mainly induced apoptosis, while zafirlukast mainly exerted its action on cell cycle. However, the precise mechanisms responsible for such different effects remain unclear. In summary, our results suggest that CysLT plays a role in proliferation and survivability of breast cancer cells in the absence of hormonal stimuli.
- Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP. [Journal Article]
- SRSci Rep 2017 Nov 10; 7(1):15307
- The sodium taurocholate co-transporting polypeptide (NTCP, SLC10A1) is the main hepatic transporter of conjugated bile acids, and the entry receptor for hepatitis B virus (HBV) and hepatitis delta vi...
The sodium taurocholate co-transporting polypeptide (NTCP, SLC10A1) is the main hepatic transporter of conjugated bile acids, and the entry receptor for hepatitis B virus (HBV) and hepatitis delta virus (HDV). Myrcludex B, a synthetic peptide mimicking the NTCP-binding domain of HBV, effectively blocks HBV and HDV infection. In addition, Myrcludex B inhibits NTCP-mediated bile acid uptake, suggesting that also other NTCP inhibitors could potentially be a novel treatment of HBV/HDV infection. This study aims to identify clinically-applied compounds intervening with NTCP-mediated bile acid transport and HBV/HDV infection. 1280 FDA/EMA-approved drugs were screened to identify compounds that reduce uptake of taurocholic acid and lower Myrcludex B-binding in U2OS cells stably expressing human NTCP. HBV/HDV viral entry inhibition was studied in HepaRG cells. The four most potent inhibitors of human NTCP were rosiglitazone (IC50 5.1 µM), zafirlukast (IC50 6.5 µM), TRIAC (IC50 6.9 µM), and sulfasalazine (IC50 9.6 µM). Chicago sky blue 6B (IC50 7.1 µM) inhibited both NTCP and ASBT, a distinct though related bile acid transporter. Rosiglitazone, zafirlukast, TRIAC, sulfasalazine, and chicago sky blue 6B reduced HBV/HDV infection in HepaRG cells in a dose-dependent manner. Five out of 1280 clinically approved drugs were identified that inhibit NTCP-mediated bile acid uptake and HBV/HDV infection in vitro.
- Neuropsychiatric Events Associated with Leukotriene-Modifying Agents: A Systematic Review. [Review]
- DSDrug Saf 2018; 41(3):253-265
- CONCLUSIONS: The risk of NEs was not quantified, because of the lack of randomized controlled trials and observational studies investigating the association.Many pharmacovigilance studies have been conducted to determine the association between NEs and LTMAs, but there is limited evidence from observational studies. High-quality epidemiological studies should be conducted to evaluate the association and quantify the risk, not only in children, but also in adults.
- Statistical investigation of the full concentration range of fasted and fed simulated intestinal fluid on the equilibrium solubility of oral drugs. [Journal Article]
- EJEur J Pharm Sci 2018 Jan 01; 111:247-256
- Upon oral administration the solubility of a drug in intestinal fluid is a key property influencing bioavailability. It is also recognised that simple aqueous solubility does not reflect intestinal s...
Upon oral administration the solubility of a drug in intestinal fluid is a key property influencing bioavailability. It is also recognised that simple aqueous solubility does not reflect intestinal solubility and to optimise in vitro investigations simulated intestinal media systems have been developed. Simulated intestinal media which can mimic either the fasted or fed state consists of multiple components each of which either singly or in combination may influence drug solubility, a property that can be investigated by a statistical design of experiment technique. In this study a design of experiment covering the full range from the lower limit of fasted to the upper limit of fed parameters and using a small number of experiments has been performed. The measured equilibrium solubility values are comparable with literature values for simulated fasted and fed intestinal fluids as well as human fasted and fed intestinal fluids. The equilibrium solubility data range is statistically equivalent to a combination of published fasted and fed design of experiment data in six (indomethacin, phenytoin, zafirlukast, carvedilol, fenofibrate and probucol) drugs with three (aprepitant, tadalafil and felodipine) drugs not equivalent. In addition the measured equilibrium solubility data sets were not normally distributed. Further studies will be required to determine the reasons for these results however it implies that a single solubility measurement without knowledge of the solubility distribution will be of limited value. The statistically significant media factors which promote equilibrium solubility (pH, sodium oleate and bile salt) were in agreement with published results but the number of determined significant factors and factor interactions was fewer in this study, lecithin for example did not influence solubility. This may be due to the reduction in statistical sensitivity from the lower number of experimental data points or the fact that using the full range will examine media parameters ratios that are not biorelevant. Overall the approach will provide an estimate of the solubility range and the most important media factors but will not be equivalent to larger scale focussed studies. Further investigations will be required to determine why some drugs do not produce equivalent DoE solubility distributions, for example combined fasted and fed DoE, but this simply may be due to the complexity and individuality of the interactions between a drug and the media components.
- Effect of composition of simulated intestinal media on the solubility of poorly soluble compounds investigated by design of experiments. [Journal Article]
- EJEur J Pharm Sci 2018 Jan 01; 111:311-319
- The composition of the human intestinal fluids varies both intra- and inter-individually. This will influence the solubility of orally administered drug compounds, and hence, the absorption and effic...
The composition of the human intestinal fluids varies both intra- and inter-individually. This will influence the solubility of orally administered drug compounds, and hence, the absorption and efficacy of compounds displaying solubility limited absorption. The purpose of this study was to assess the influence of simulated intestinal fluid (SIF) composition on the solubility of poorly soluble compounds. Using a Design of Experiments (DoE) approach, a set of 24 SIF was defined within the known compositions of human fasted state intestinal fluid. The SIF were composed of phospholipid, bile salt, and different pH, buffer capacities and osmolarities. On a small scale semi-robotic system, the solubility of 6 compounds (aprepitant, carvedilol, felodipine, fenofibrate, probucol, and zafirlukast) was determined in the 24 SIF. Compound specific models, describing key factors influencing the solubility of each compound, were identified. Although all models were different, the level of phospholipid and bile salt, the pH, and the interactions between these, had the biggest influences on solubility overall. Thus, a reduction of the DoE from five to three factors was possible (11-13 media), making DoE solubility studies feasible compared to single SIF solubility studies. Applying this DoE approach will lead to a better understanding of the impact of intestinal fluid composition on the solubility of a given drug compound.
- Influence of Physiological Gastrointestinal Surfactant Ratio on the Equilibrium Solubility of BCS Class II Drugs Investigated Using a Four Component Mixture Design. [Journal Article]
- MPMol Pharm 2017 Dec 04; 14(12):4132-4144
- The absorption of poorly water-soluble drugs is influenced by the luminal gastrointestinal fluid content and composition, which control solubility. Simulated intestinal fluids have been introduced in...
The absorption of poorly water-soluble drugs is influenced by the luminal gastrointestinal fluid content and composition, which control solubility. Simulated intestinal fluids have been introduced into dissolution testing including endogenous amphiphiles and digested lipids at physiological levels; however, in vivo individual variation exists in the concentrations of these components, which will alter drug absorption through an effect on solubility. The use of a factorial design of experiment and varying media by introducing different levels of bile, lecithin, and digested lipids has been previously reported, but here we investigate the solubility variation of poorly soluble drugs through more complex biorelevant amphiphile interactions. A four-component mixture design was conducted to understand the solubilization capacity and interactions of bile salt, lecithin, oleate, and monoglyceride with a constant total concentration (11.7 mM) but varying molar ratios. The equilibrium solubility of seven low solubility acidic (zafirlukast), basic (aprepitant, carvedilol), and neutral (fenofibrate, felodipine, griseofulvin, and spironolactone) drugs was investigated. Solubility results are comparable with literature values and also our own previously published design of experiment studies. Results indicate that solubilization is not a sum accumulation of individual amphiphile concentrations, but a drug specific effect through interactions of mixed amphiphile compositions with the drug. This is probably due to a combined interaction of drug characteristics; for example, lipophilicity, molecular shape, and ionization with amphiphile components, which can generate specific drug-micelle affinities. The proportion of each component can have a remarkable influence on solubility with, in some cases, the highest and lowest points close to each other. A single-point solubility measurement in a fixed composition simulated media or human intestinal fluid sample will therefore provide a value without knowledge of the surrounding solubility topography meaning that variability may be overlooked. This study has demonstrated how the amphiphile ratios influence drug solubility and highlights the importance of the envelope of physiological variation when simulating in vivo drug behavior.
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- Validation of Dissolution Testing with Biorelevant Media: An OrBiTo Study. [Journal Article]
- MPMol Pharm 2017 Dec 04; 14(12):4192-4201
- Dissolution testing with biorelevant media has become widespread in the pharmaceutical industry as a means of better understanding how drugs and formulations behave in the gastrointestinal tract. Unt...
Dissolution testing with biorelevant media has become widespread in the pharmaceutical industry as a means of better understanding how drugs and formulations behave in the gastrointestinal tract. Until now, however, there have been few attempts to gauge the reproducibility of results obtained with these methods. The aim of this study was to determine the interlaboratory reproducibility of biorelevant dissolution testing, using the paddle apparatus (USP 2). Thirteen industrial and three academic laboratories participated in this study. All laboratories were provided with standard protocols for running the tests: dissolution in FaSSGF to simulate release in the stomach, dissolution in a single intestinal medium, FaSSIF, to simulate release in the small intestine, and a "transfer" (two-stage) protocol to simulate the concentration profile when conditions are changed from the gastric to the intestinal environment. The test products chosen were commercially available ibuprofen tablets and zafirlukast tablets. The biorelevant dissolution tests showed a high degree of reproducibility among the participating laboratories, even though several different batches of the commercially available medium preparation powder were used. Likewise, results were almost identicalbetween the commercial biorelevant media and those produced in-house. Comparing results to previous ring studies, including those performed with USP calibrator tablets or commercially available pharmaceutical products in a single medium, the results for the biorelevant studies were highly reproducible on an interlaboratory basis. Interlaboratory reproducibility with the two-stage test was also acceptable, although the variability was somewhat greater than with the single medium tests. Biorelevant dissolution testing is highly reproducible among laboratories and can be relied upon for cross-laboratory comparisons.