The Experts below are selected from a list of 234 Experts worldwide ranked by ideXlab platform

Stefan Laufer - One of the best experts on this subject based on the ideXlab platform.

  • The Investigation of Lipoxygenases as Therapeutic Targets in Malignant Pleural Mesothelioma
    Pathology & Oncology Research, 2019
    Co-Authors: Lily Oguh-olayinka, Stefan Laufer, Vijay Agarwal, Dulani Ranatunge, Anne Campbell, Lynn Cawkwell, Michael J. Lind
    Abstract:

    Advanced malignant pleural mesothelioma (MPM) has an extremely poor prognosis with limited chemotherapy options, therefore the identification of new therapeutic targets would aid in disease management. Arachidonic acid is metabolised by cyclooxygenase and lipoxygenase enzymes. The lipoxygenase isoenzymes 5-LOX and 12-LOX have been implicated in carcinogenesis. We aimed to examine 5-LOX and 12-LOX protein expression in a large retrospective series of mesothelioma samples. Further to this, the in vitro cytotoxic effects of lipoxygenase pathway inhibitors were investigated in mesothelioma cells. Archival samples from 83 patients with MPM were examined by immunohistochemistry for expression of the 5-LOX and 12-LOX proteins. The MTS assay was used to assess cell viability following 72 h treatment with the lipoxygenase pathway inhibitors baicalein, Licofelone, MK-886 and zileuton in the MPM cell lines NCI-H2052, NCI-H2452 and MSTO-211H. Positive 12-LOX protein expression was recorded in 69/83 (83%) and positive 5-LOX expression was observed in 56/77 (73%) of MPM tissue samples. Co-expression of 5-LOX with 12-LOX was seen in 46/78 (58%) of MPM samples. Positive expression of 5-LOX, 12-LOX and COX-2 proteins was identified in the NCI-H2052, NCI-H2452 and MSTO-211H MPM cell lines. Baicalein (12-LOX and 15-LOX inhibitor) was effective in 3/3 MPM cell lines at low concentrations with an IC50 range of 9.6 μM to 20.7 μM. We have demonstrated that the 5-LOX and 12-LOX proteins are expressed in a significant proportion of MPM samples (73% and 83% respectively) and may represent novel therapeutic targets in this disease. We have demonstrated that the inhibition of the LOX pathway using baicalein may be effective as a novel treatment for MPM, however further human pharmacokinetic studies are required in order to establish whether the concentration used in vitro is clinically achievable.

  • The Journal of Rheumatology Volume 29, no. 7
    2016
    Co-Authors: Stefan Laufer, Johanne Martel-pelletier, Christelle Boileau, Jean-pierre Pelletier, Susanne Tries, Jean-yves Jouzeau, Patrick Netter
    Abstract:

    osteoarthritis: inhibition of pro-apoptotic factors. reduces the level of cartilage chondrocyte death in vivo in experimental dog Licofelone (ML-3000), a dual inhibitor of 5-lipoxygenase and cyclooxygenase

  • the decrease of cell membrane fluidity by the non steroidal anti inflammatory drug Licofelone inhibits epidermal growth factor receptor signalling and triggers apoptosis in hca 7 colon cancer cells
    Cancer Letters, 2012
    Co-Authors: Simona Tavolari, Stefan Laufer, Alessandra Munarini, Gianluca Storci, Pasquale Chieco, Tiziana Guarnieri
    Abstract:

    The ability to induce changes in cell membrane properties is nowadays considered an additional mechanism to explain the pharmacological effects of non-steroidal anti-inflammatory drugs (NSAIDs). We previously demonstrated that the NSAID Licofelone, a dual cyclooxygenase/5-lipoxygenase inhibitor, triggers apoptosis in HCA-7 colon cancer cells independently from the inhibition of these enzymes. Here, we provide evidence that, in HCA-7 cells, the pro-apoptotic effect of this drug relies, at least in part, on its ability to inhibit epidermal growth factor receptor (EGFR) signalling by a decrease of cell membrane fluidity. Indeed, Licofelone induced a relevant change in the relative proportions of some saturated, monounsaturated and polyunsaturated fatty acids constituting HCA-7 phospholipid fraction and significantly increased the levels of cholesterol in HCA-7 cell membrane. All of these changes resulted in a remarkable decrease of membrane fluidity. Such phenomenon was associated with the block of EGFR kinase activity and of its downstream targets, the p44-42 mitogen-activated protein kinase (MAPK) and AKT cascades, whose inhibitions were found to induce apoptosis in HCA-7 cells. Overall, these findings provide a new additional mechanism by which NSAIDs are effective toward colon cancer cells.

  • protective effects of Licofelone a 5 lipoxygenase and cyclo oxygenase inhibitor versus naproxen on cartilage loss in knee osteoarthritis a first multicentre clinical trial using quantitative mri
    Annals of the Rheumatic Diseases, 2009
    Co-Authors: Jeanpierre Raynauld, Johanne Martelpelletier, Stefan Laufer, Peter Bias, Boulos Haraoui, D Choquette, Andre Beaulieu, Francois Abram, Marc Dorais, E Vignon
    Abstract:

    OBJECTIVE: In a multicentre study to explore the effects of Licofelone as a disease-modifying osteoarthritis drug in comparison with naproxen in patients with knee osteoarthritis (OA), using MRI and x-ray examination. METHODS: Patients with knee OA (n = 355) were randomised to receive either Licofelone (200 mg twice a day) or naproxen (500 mg twice a day). MRI and x-ray examinations were performed at baseline, 6 months (MRI only), 12 and 24 months. MRI was used to assess quantitatively changes in cartilage volume, and x-ray examinations (Lyon-Schuss) to measure changes in the mean and minimum joint space width (JSW) in the medial compartment. Questionnaires probing symptoms were completed. Data were presented as intention to treat (ITT) and according to protocol (ATP). RESULTS: Cartilage volume loss in the global joint and medial and lateral compartments was significantly less in the Licofelone than in the naproxen group for ITT at 12 and 24 months and for ATP at all times except in the medial compartment. Patients with medial meniscal extrusion had a greater loss of cartilage volume. In these patients, Licofelone markedly reduced the cartilage loss for both ITT and ATP at 12 and 24 months. Although Licofelone showed less reduction in the JSW than naproxen, this did not reach significance. All clinical variables were improved at 24 months (p<0.001) for both groups, with a good safety profile. CONCLUSION: Licofelone and naproxen were equally effective in reducing OA symptoms; however, Licofelone significantly reduced cartilage volume loss over time, thus having a protective effect in patients with knee OA. This study proves the superiority of quantitative MRI over x-ray examinations in a multicentre clinical trial.

  • Licofelone suppresses prostaglandin e2 formation by interference with the inducible microsomal prostaglandin e2 synthase 1
    Journal of Pharmacology and Experimental Therapeutics, 2008
    Co-Authors: Andreas Koeberle, Stefan Laufer, Wolfgang Albrecht, Ulf Siemoneit, Ulrike Buhring, Hinnak Northoff, Oliver Werz
    Abstract:

    The anti-inflammatory drug Licofelone [=ML3000; 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1 H -pyrrolizin-5-yl] acetic acid], currently undergoing phase III trials for osteoarthritis, inhibits the prostaglandin (PG) and leukotriene biosynthetic pathway. Licofelone was reported to suppress the formation of PGE2 in various cell-based test systems, but the underlying molecular mechanisms are not entirely clear. Here, we examined the direct interference of Licofelone with enzymes participating in PGE2 biosynthesis, that is, cyclooxygenase (COX)-1 and COX-2 as well as microsomal PGE2 synthase (mPGES)-1. Licofelone concentration-dependently inhibited isolated COX-1 (IC50 = 0.8 μM), whereas isolated COX-2 was less affected (IC50 > 30 μM). However, Licofelone efficiently blocked the conversion of PGH2 to PGE2 mediated by mPGES-1 (IC50 = 6 μM) derived from microsomes of interleukin-1β-treated A549 cells, being about equipotent to 3-[1-(4-chlorobenzyl)-3- t -butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid (MK-886), a well recognized mPGES-1 inhibitor. In intact interleukin-1β-treated A549 cells, Licofelone potently (IC50 < 1 μM) blocked formation of PGE2 in response to calcimycin (A23187) plus exogenous arachidonic acid, but the concomitant generation of 6-keto PGF1α, used as a biomarker for COX-2 activity, was not inhibited. We conclude that Licofelone suppresses inflammatory PGE2 formation preferentially by inhibiting mPGES-1 at concentrations that do not affect COX-2, implying an attractive and thus far unique molecular pharmacological dynamics as inhibitor of COX-1, the 5-lipoxygenase pathway, and of mPGES-1.

Wolfgang Albrecht - One of the best experts on this subject based on the ideXlab platform.

  • Licofelone suppresses prostaglandin e2 formation by interference with the inducible microsomal prostaglandin e2 synthase 1
    Journal of Pharmacology and Experimental Therapeutics, 2008
    Co-Authors: Andreas Koeberle, Stefan Laufer, Wolfgang Albrecht, Ulf Siemoneit, Ulrike Buhring, Hinnak Northoff, Oliver Werz
    Abstract:

    The anti-inflammatory drug Licofelone [=ML3000; 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1 H -pyrrolizin-5-yl] acetic acid], currently undergoing phase III trials for osteoarthritis, inhibits the prostaglandin (PG) and leukotriene biosynthetic pathway. Licofelone was reported to suppress the formation of PGE2 in various cell-based test systems, but the underlying molecular mechanisms are not entirely clear. Here, we examined the direct interference of Licofelone with enzymes participating in PGE2 biosynthesis, that is, cyclooxygenase (COX)-1 and COX-2 as well as microsomal PGE2 synthase (mPGES)-1. Licofelone concentration-dependently inhibited isolated COX-1 (IC50 = 0.8 μM), whereas isolated COX-2 was less affected (IC50 > 30 μM). However, Licofelone efficiently blocked the conversion of PGH2 to PGE2 mediated by mPGES-1 (IC50 = 6 μM) derived from microsomes of interleukin-1β-treated A549 cells, being about equipotent to 3-[1-(4-chlorobenzyl)-3- t -butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid (MK-886), a well recognized mPGES-1 inhibitor. In intact interleukin-1β-treated A549 cells, Licofelone potently (IC50 < 1 μM) blocked formation of PGE2 in response to calcimycin (A23187) plus exogenous arachidonic acid, but the concomitant generation of 6-keto PGF1α, used as a biomarker for COX-2 activity, was not inhibited. We conclude that Licofelone suppresses inflammatory PGE2 formation preferentially by inhibiting mPGES-1 at concentrations that do not affect COX-2, implying an attractive and thus far unique molecular pharmacological dynamics as inhibitor of COX-1, the 5-lipoxygenase pathway, and of mPGES-1.

  • in vitro metabolism of 2 6 4 chlorophenyl 2 2 dimethyl 7 phenyl 2 3 dihydro 1h pyrrolizin 5 yl acetic acid Licofelone ml3000 an inhibitor of cyclooxygenase 1 and 2 and 5 lipoxygenase
    Drug Metabolism and Disposition, 2008
    Co-Authors: Wolfgang Albrecht, Anke Unger, Andreas K. Nussler, Stefan Laufer
    Abstract:

    2-[6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid (Licofelone) is a dual inhibitor of both cyclooxygenase isoforms and 5-lipoxygenase and under development for treatment of osteoarthritis. In conventional in vitro assays using liver microsomes and NADPH as cosubstrate, a high metabolic stability of Licofelone was observed. In the presence of UDP-glucuronic acid, Licofelone is rapidly converted into the corresponding acyl glucuronide, M1. These results are in conflict with data from clinical studies. After administration of Licofelone to humans, M1 plasma concentrations were negligibly low, whereas the exposure of the hydroxy-metabolite M2 achieved values of approximately 20% compared with that of the parent drug. Metabolism studies with human hepatocytes and dual-activity assays with microsomes, which allowed the simultaneous monitoring of hydroxylation and glucuronidation reactions, were performed, and the metabolic pathway of Licofelone was elucidated. After glucuronidation, predominantly catalyzed by UDP glucuronosyltransferase (UGT) isoforms UGT2B7, UGT1A9, and UGT1A3, M1 is converted into the hydroxy-glucuronide M3 in a CYP2C8-dependent reaction. The enzyme specificities were investigated using recombinant human cytochrome P450 and UGT isoforms as test systems. In vitro drug-interaction studies using the 6α-hydroxylation of paclitaxel as control reaction confirmed that neither Licofelone nor M1 is a relevant inhibitor of CYP2C8. The formation of M3 was also observed with liver microsomes from cynomolgus monkeys, but in incubations with mouse and rat liver microsomes, M1 remained unchanged. The clinical relevance of these findings is discussed.

  • In Vitro Metabolism of 2-[6-(4-Chlorophenyl)-2,2-dimethyl-7- phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] Acetic Acid (Licofelone, ML3000), an Inhibitor of Cyclooxygenase-1 and-2 and 5-Lipoxygenase
    2008
    Co-Authors: Wolfgang Albrecht, Anke Unger, Andreas K. Nussler, Stefan Laufer
    Abstract:

    pyrrolizin-5-yl] acetic acid (Licofelone) is a dual inhibitor of both cyclooxygenase isoforms and 5-lipoxygenase and under develop-ment for treatment of osteoarthritis. In conventional in vitro assays using liver microsomes and NADPH as cosubstrate, a high meta-bolic stability of Licofelone was observed. In the presence of UDP-glucuronic acid, Licofelone is rapidly converted into the corre-sponding acyl glucuronide, M1. These results are in conflict with data from clinical studies. After administration of Licofelone to humans, M1 plasma concentrations were negligibly low, whereas the exposure of the hydroxy-metabolite M2 achieved values of approximately 20 % compared with that of the parent drug. Metab-olism studies with human hepatocytes and dual-activity assays with microsomes, which allowed the simultaneous monitoring of hydroxylation and glucuronidation reactions, were performed, and the metabolic pathway of Licofelone was elucidated. After gluc

  • Licofelone a novel 5 lox cox inhibitor attenuates leukocyte rolling and adhesion on endothelium under flow
    Biochemical Pharmacology, 2005
    Co-Authors: Holger Ulbrich, Stefan Laufer, Oliver Soehnlein, Xun Xie, Einar E Eriksson, Lennart Lindbom, Wolfgang Albrecht, Gerd Dannhardt
    Abstract:

    Abstract The main mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of cycloxygenases COX-1 and COX-2. During recent years, combined 5-LOX/COX-inhibition, interfering with the biosynthesis of both prostaglandins and leukotrienes (LTs), has emerged as a possibility to avoid side effects related to COX-inhibition. The aim of the present study was to investigate if there is a contribution of mechanisms other than the reduction of inflammatory prostaglandins and leukotrienes to the anti-inflammatory effect of the LOX/COX inhibitor Licofelone. In a flow chamber assay, Licofelone (10–30 μM) dose-dependently decreased both the rolling and adhesion of leukocytes on endothelial cells (EC). In contrast, no effects were found after treatment of EC with the unselective COX-1/COX-2 inhibitor indomethacin (30 μM), the potent and selective 5-LOX inhibitor, ZD-2138 (30 μM), the mainly COX-2 inhibitor aceclofenac (30 μM), the selective COX-2 inhibitor celecoxib (30 μM) and the combination of ZD-2138 with the selective COX-2 inhibitor celecoxib (30 μM). In the presence of Licofelone (30 μM) the expression of E-selectin mRNA in cytokine-stimulated EC was attenuated, whereas no NSAID (30 μM) tested showed any effect on E-selectin expression. Moreover, Licofelone treatment (30 μM) attenuated expression of VCAM-1 and ICAM-1 on inflammatory EC. The effect of Licofelone on leukocyte recruitment was also evaluated in vivo. Using a mouse peritonitis model it was found that leukocyte accumulation was markedly reduced in Licofelone treated animals (100 mg/kg) compared to untreated mice. Thus, the novel 5-LOX/COX inhibitor Licofelone possesses anti-inflammatory activity that, in addition to COX/LOX inhibition, involves effects on leukocyte-endothelial interactions.

Yuting Zhang - One of the best experts on this subject based on the ideXlab platform.

  • abstract 2625 simultaneous targeting of odc and 5 lox cox block the tobacco carcinogen induced lung adenoma progression to adenocarcinoma in a j mice
    Cancer Research, 2016
    Co-Authors: Gaurav Kumar, Jagan Mohan R Patolla, Venkateshwar Madka, Altaf Mohammed, Li Qian, Yuting Zhang, Laura Biddick, Anil Singh, Allison F Gillaspy, Stanley Lightfoot
    Abstract:

    Increased polyamine synthesis and inflammation have long been associated with intraepithelial neoplasia and their progression to malignant tumor growth, including lung cancer. Targeting multiple pathways simultaneously with low-dose combinations may be an effective approach to modulate different pathways and their downstream signaling, which may result in an increased efficacy and reduced side effects than a single-agent high dose strategy. The aim of the present study was to investigate the effects of DFMO (ODC inhibitor) and Licofelone, a dual 5-LOX-COX inhibitor, individually and in combination, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone NNK-induced lung adenoma and progression to adenocarcinoma in female A/J mice. At 6 weeks of age, mice (25 /group) were fed AIN-76A-modified diet, and one week later, lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 μmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed with either control or experimental diets containing DFMO (1500 or 3000 ppm) or Licofelone (200 or 400 ppm) or combination of low doses of DFMO and Licofelone. Mice were killed after 17 or 34 weeks of drug exposure and tumors were evaluated via histopathology and lung tumors were assayed for modification of various biomarkers of proliferation and apoptosis. Results suggest that both DFMO and Licofelone showed dose-dependent inhibition of NNK-induced lung adenoma progression to adenocarcinoma. At high dose DFMO and Licofelone showed 46% and 55% of adenocarcinoma inhibition. Importantly, low dose combination of DFMO and Licofelone showed more pronounced effects at both 17 or 34 weeks in inhibiting the total adenocarcinomas (adenoma and adenocarcinoma progression) by >65% and somewhat in a synergistic manner as compared to individual low doses of DFMO and Licofelone. Combination-treated lung tumors exhibited modulation of ODC pathway key components (Arg1, Oat, Oaz, SRM, SMS, and SAT) along with decreased proliferation (PCNA, cyclin D1 and Cyclin A) and increased expression of p53, p21 and p27 compared to tumors from mice fed with control diet. These data suggest that targeting ODC plus 5-LOX/COX decreases the progression of adenoma to adenocarcinoma. Furthermore, adenoma progression delay by combination of DFMO and Licofelone is associated with decreased tumor invasive markers such as MMTPs and EMT markers. In conclusion, targeting two or more pathways is an effective chemopreventive approach for high-risk lung cancer individual9s particularly former tobacco smokers with lung hyperplasia and adenomas. (Supported by Kerley-Cade Chair Endowment and NCI-N01-CN-53300) Citation Format: Gaurav Kumar, Jagan Mohan R. Patolla, Venkateshwar Madka, Altaf Mohammed, Li Qian, Yuting Zhang, Laura Biddick, Anil Singh, Allison Gillaspy, Stanley Lightfoot, Levy Kopelovich, Vernon E. Steele, Chinthalapally V. Rao. Simultaneous targeting of ODC and 5-LOX/COX block the tobacco carcinogen-induced lung adenoma progression to adenocarcinoma in A/J mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2625.

  • simultaneous targeting of 5 lox cox and odc block nnk induced lung adenoma progression to adenocarcinoma in a j mice
    American Journal of Cancer Research, 2016
    Co-Authors: Gaurav Kumar, Venkateshwar Madka, Altaf Mohammed, Yuting Zhang, Laura Biddick, Anil Singh, Allison F Gillaspy, Stanley Lightfoot, Jagan M R Patlolla, Vernon E Steele
    Abstract:

    Lung cancer is the leading cause of cancer deaths worldwide. Targeting complementary pathways will achieve better treatment efficacy than a single agent high-dose strategy that could increase risk of side effects and tumor resistance. To target COX-2, 5-LOX, and ODC simultaneously, we tested the effects of a dual 5-LOX-COX inhibitor, Licofelone, and an ODC inhibitor, DFMO, alone and in combination, on NNK-induced lung tumors in female A/J mice. Seven-week-old mice were treated with NNK (10 μmol/mouse, single dose, i.p.) and randomized to different treatment groups. Three weeks after injection, mice were fed control or experimental diets (DFMO 1500/3000 ppm, Licofelone 200/400 ppm, or a low-dose combination of 1500 ppm DFMO and 200 ppm Licofelone) for 17 or 34 weeks. Both agents significantly inhibited tumor formation in a dose-dependent manner. As anticipated more adenomas and adenocarcinomas were observed at 17 and 34 weeks, respectively. Importantly, low dose combination of DFMO and Licofelone showed more pronounced effects at 17 or 34 weeks in inhibiting the total tumor formation (~60%, p < 0.0001) and adenocarcinoma (~65%, p < 0.0001) compared to individual high dose of DFMO (~44% and 46%, p < 0.0001) and Licofelone (~48% and 55%, p < 0.0001). DFMO and combination-treated mice lung tumors exhibited modulated ODC pathway components (Oat, Oaz, SRM, SMS, and SAT, p < 0.05) along with decreased proliferation (PCNA, Cyclin D1 and Cyclin A) and increased expression of p53, p21 and p27 compared to mice fed control diet. Both DFMO and Licofelone significantly inhibited tumor inflammatory markers. Our findings suggest that a low-dose combined treatment targeting inflammation and polyamine synthesis may provide effective chemoprevention.

  • abstract lb 182 Licofelone inhibits nnk induced lung adenocarcinoma formation in a j mice by suppressing cox lox and inhibits human lung cancer cell growth by p21 up regulation
    Cancer Research, 2013
    Co-Authors: Jagan M R Patlolla, Dhimant Desai, Shantu Amin, Li Qian, Yuting Zhang, Laura Biddick, Stan Lightfoot, Levy Kopelovich, Chinthalapally V Rao
    Abstract:

    Lung cancer is the leading causes of cancer deaths. Inflammation plays an important role in lung tumor progression; in that eicosanoids levels derived from cyclooxygenase (COX)-2 and 5-lipoxygenase (LOX) positively influence the tumor growth. We have evaluated chemopreventive effects of a novel dual LOX/ COX inhibitor, Licofelone {[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung adenoma and adenocarcinoma formation in female A/J mice and its possible mode of action was evaluated using human lung cancer cell line A549. For bioassay, at 6 weeks of age, mice were randomized and fed control AIN-76A modified diet. At 7 weeks of age (25-mice/group) intended for carcinogen treatment received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after the NNK treatment, groups intended for Licofelone treatment were administered 200 and 400 ppm in diet for either 17 weeks (10 mice/group) and/or 34 weeks (15 mice/group) to assess efficacy against lung adenoma and adenocarcinoma. Intervention with 200 or 400 ppm Licofelone significantly suppressed lung adenomas by 29% (p . These results suggest that Licofelone a dual 5LOX/COX inhibitor inhibits the NNK induced lung adenomas and more so by suppressing adenocarcinoma formation in a dose-dependent manner. IHC analysis of lung tumors from NNK treated mice exposed to Licofelone showed a significantly reduced proliferating cell nuclear antigen (PCNA) positive index, increased TUNEL positive cells and p21 expression as compared to lung adenocarcinomas from NNK treated mice fed with control diet. Treatment with Licofelone significantly suppressed both COX and 5-LOX expression and its metabolite formation in NNK induced lung tumors and human lung cancer cell line growth inhibition was associated with p21-upregulation. These findings suggest that dietary Licofelone inhibits tobacco carcinogen-induced lung adenoma and adenocarcinoma formation in a dose-dependent manner by modulating COX-2 and 5-LOX activities. {Supported by NIH, NCI grants NO1-CN-53300 and Kerley-Cade Chair} Citation Format: Jagan Mohan Reddy Patlolla, Levy Kopelovich, Li Qian, Laura Biddick, Yuting Zhang, Dhimant Desai, Shantu Amin, Stan Lightfoot, Chinthalapally V. Rao. Licofelone inhibits NNK-induced lung adenocarcinoma formation in A/J mice by suppressing COX/LOX and inhibits human lung cancer cell growth by p21 up-regulation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-182. doi:10.1158/1538-7445.AM2013-LB-182

Laura Biddick - One of the best experts on this subject based on the ideXlab platform.

  • abstract 2625 simultaneous targeting of odc and 5 lox cox block the tobacco carcinogen induced lung adenoma progression to adenocarcinoma in a j mice
    Cancer Research, 2016
    Co-Authors: Gaurav Kumar, Jagan Mohan R Patolla, Venkateshwar Madka, Altaf Mohammed, Li Qian, Yuting Zhang, Laura Biddick, Anil Singh, Allison F Gillaspy, Stanley Lightfoot
    Abstract:

    Increased polyamine synthesis and inflammation have long been associated with intraepithelial neoplasia and their progression to malignant tumor growth, including lung cancer. Targeting multiple pathways simultaneously with low-dose combinations may be an effective approach to modulate different pathways and their downstream signaling, which may result in an increased efficacy and reduced side effects than a single-agent high dose strategy. The aim of the present study was to investigate the effects of DFMO (ODC inhibitor) and Licofelone, a dual 5-LOX-COX inhibitor, individually and in combination, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone NNK-induced lung adenoma and progression to adenocarcinoma in female A/J mice. At 6 weeks of age, mice (25 /group) were fed AIN-76A-modified diet, and one week later, lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 μmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed with either control or experimental diets containing DFMO (1500 or 3000 ppm) or Licofelone (200 or 400 ppm) or combination of low doses of DFMO and Licofelone. Mice were killed after 17 or 34 weeks of drug exposure and tumors were evaluated via histopathology and lung tumors were assayed for modification of various biomarkers of proliferation and apoptosis. Results suggest that both DFMO and Licofelone showed dose-dependent inhibition of NNK-induced lung adenoma progression to adenocarcinoma. At high dose DFMO and Licofelone showed 46% and 55% of adenocarcinoma inhibition. Importantly, low dose combination of DFMO and Licofelone showed more pronounced effects at both 17 or 34 weeks in inhibiting the total adenocarcinomas (adenoma and adenocarcinoma progression) by >65% and somewhat in a synergistic manner as compared to individual low doses of DFMO and Licofelone. Combination-treated lung tumors exhibited modulation of ODC pathway key components (Arg1, Oat, Oaz, SRM, SMS, and SAT) along with decreased proliferation (PCNA, cyclin D1 and Cyclin A) and increased expression of p53, p21 and p27 compared to tumors from mice fed with control diet. These data suggest that targeting ODC plus 5-LOX/COX decreases the progression of adenoma to adenocarcinoma. Furthermore, adenoma progression delay by combination of DFMO and Licofelone is associated with decreased tumor invasive markers such as MMTPs and EMT markers. In conclusion, targeting two or more pathways is an effective chemopreventive approach for high-risk lung cancer individual9s particularly former tobacco smokers with lung hyperplasia and adenomas. (Supported by Kerley-Cade Chair Endowment and NCI-N01-CN-53300) Citation Format: Gaurav Kumar, Jagan Mohan R. Patolla, Venkateshwar Madka, Altaf Mohammed, Li Qian, Yuting Zhang, Laura Biddick, Anil Singh, Allison Gillaspy, Stanley Lightfoot, Levy Kopelovich, Vernon E. Steele, Chinthalapally V. Rao. Simultaneous targeting of ODC and 5-LOX/COX block the tobacco carcinogen-induced lung adenoma progression to adenocarcinoma in A/J mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2625.

  • simultaneous targeting of 5 lox cox and odc block nnk induced lung adenoma progression to adenocarcinoma in a j mice
    American Journal of Cancer Research, 2016
    Co-Authors: Gaurav Kumar, Venkateshwar Madka, Altaf Mohammed, Yuting Zhang, Laura Biddick, Anil Singh, Allison F Gillaspy, Stanley Lightfoot, Jagan M R Patlolla, Vernon E Steele
    Abstract:

    Lung cancer is the leading cause of cancer deaths worldwide. Targeting complementary pathways will achieve better treatment efficacy than a single agent high-dose strategy that could increase risk of side effects and tumor resistance. To target COX-2, 5-LOX, and ODC simultaneously, we tested the effects of a dual 5-LOX-COX inhibitor, Licofelone, and an ODC inhibitor, DFMO, alone and in combination, on NNK-induced lung tumors in female A/J mice. Seven-week-old mice were treated with NNK (10 μmol/mouse, single dose, i.p.) and randomized to different treatment groups. Three weeks after injection, mice were fed control or experimental diets (DFMO 1500/3000 ppm, Licofelone 200/400 ppm, or a low-dose combination of 1500 ppm DFMO and 200 ppm Licofelone) for 17 or 34 weeks. Both agents significantly inhibited tumor formation in a dose-dependent manner. As anticipated more adenomas and adenocarcinomas were observed at 17 and 34 weeks, respectively. Importantly, low dose combination of DFMO and Licofelone showed more pronounced effects at 17 or 34 weeks in inhibiting the total tumor formation (~60%, p < 0.0001) and adenocarcinoma (~65%, p < 0.0001) compared to individual high dose of DFMO (~44% and 46%, p < 0.0001) and Licofelone (~48% and 55%, p < 0.0001). DFMO and combination-treated mice lung tumors exhibited modulated ODC pathway components (Oat, Oaz, SRM, SMS, and SAT, p < 0.05) along with decreased proliferation (PCNA, Cyclin D1 and Cyclin A) and increased expression of p53, p21 and p27 compared to mice fed control diet. Both DFMO and Licofelone significantly inhibited tumor inflammatory markers. Our findings suggest that a low-dose combined treatment targeting inflammation and polyamine synthesis may provide effective chemoprevention.

  • abstract lb 182 Licofelone inhibits nnk induced lung adenocarcinoma formation in a j mice by suppressing cox lox and inhibits human lung cancer cell growth by p21 up regulation
    Cancer Research, 2013
    Co-Authors: Jagan M R Patlolla, Dhimant Desai, Shantu Amin, Li Qian, Yuting Zhang, Laura Biddick, Stan Lightfoot, Levy Kopelovich, Chinthalapally V Rao
    Abstract:

    Lung cancer is the leading causes of cancer deaths. Inflammation plays an important role in lung tumor progression; in that eicosanoids levels derived from cyclooxygenase (COX)-2 and 5-lipoxygenase (LOX) positively influence the tumor growth. We have evaluated chemopreventive effects of a novel dual LOX/ COX inhibitor, Licofelone {[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung adenoma and adenocarcinoma formation in female A/J mice and its possible mode of action was evaluated using human lung cancer cell line A549. For bioassay, at 6 weeks of age, mice were randomized and fed control AIN-76A modified diet. At 7 weeks of age (25-mice/group) intended for carcinogen treatment received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after the NNK treatment, groups intended for Licofelone treatment were administered 200 and 400 ppm in diet for either 17 weeks (10 mice/group) and/or 34 weeks (15 mice/group) to assess efficacy against lung adenoma and adenocarcinoma. Intervention with 200 or 400 ppm Licofelone significantly suppressed lung adenomas by 29% (p . These results suggest that Licofelone a dual 5LOX/COX inhibitor inhibits the NNK induced lung adenomas and more so by suppressing adenocarcinoma formation in a dose-dependent manner. IHC analysis of lung tumors from NNK treated mice exposed to Licofelone showed a significantly reduced proliferating cell nuclear antigen (PCNA) positive index, increased TUNEL positive cells and p21 expression as compared to lung adenocarcinomas from NNK treated mice fed with control diet. Treatment with Licofelone significantly suppressed both COX and 5-LOX expression and its metabolite formation in NNK induced lung tumors and human lung cancer cell line growth inhibition was associated with p21-upregulation. These findings suggest that dietary Licofelone inhibits tobacco carcinogen-induced lung adenoma and adenocarcinoma formation in a dose-dependent manner by modulating COX-2 and 5-LOX activities. {Supported by NIH, NCI grants NO1-CN-53300 and Kerley-Cade Chair} Citation Format: Jagan Mohan Reddy Patlolla, Levy Kopelovich, Li Qian, Laura Biddick, Yuting Zhang, Dhimant Desai, Shantu Amin, Stan Lightfoot, Chinthalapally V. Rao. Licofelone inhibits NNK-induced lung adenocarcinoma formation in A/J mice by suppressing COX/LOX and inhibits human lung cancer cell growth by p21 up-regulation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-182. doi:10.1158/1538-7445.AM2013-LB-182

Andreas K. Nussler - One of the best experts on this subject based on the ideXlab platform.

  • in vitro metabolism of 2 6 4 chlorophenyl 2 2 dimethyl 7 phenyl 2 3 dihydro 1h pyrrolizin 5 yl acetic acid Licofelone ml3000 an inhibitor of cyclooxygenase 1 and 2 and 5 lipoxygenase
    Drug Metabolism and Disposition, 2008
    Co-Authors: Wolfgang Albrecht, Anke Unger, Andreas K. Nussler, Stefan Laufer
    Abstract:

    2-[6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid (Licofelone) is a dual inhibitor of both cyclooxygenase isoforms and 5-lipoxygenase and under development for treatment of osteoarthritis. In conventional in vitro assays using liver microsomes and NADPH as cosubstrate, a high metabolic stability of Licofelone was observed. In the presence of UDP-glucuronic acid, Licofelone is rapidly converted into the corresponding acyl glucuronide, M1. These results are in conflict with data from clinical studies. After administration of Licofelone to humans, M1 plasma concentrations were negligibly low, whereas the exposure of the hydroxy-metabolite M2 achieved values of approximately 20% compared with that of the parent drug. Metabolism studies with human hepatocytes and dual-activity assays with microsomes, which allowed the simultaneous monitoring of hydroxylation and glucuronidation reactions, were performed, and the metabolic pathway of Licofelone was elucidated. After glucuronidation, predominantly catalyzed by UDP glucuronosyltransferase (UGT) isoforms UGT2B7, UGT1A9, and UGT1A3, M1 is converted into the hydroxy-glucuronide M3 in a CYP2C8-dependent reaction. The enzyme specificities were investigated using recombinant human cytochrome P450 and UGT isoforms as test systems. In vitro drug-interaction studies using the 6α-hydroxylation of paclitaxel as control reaction confirmed that neither Licofelone nor M1 is a relevant inhibitor of CYP2C8. The formation of M3 was also observed with liver microsomes from cynomolgus monkeys, but in incubations with mouse and rat liver microsomes, M1 remained unchanged. The clinical relevance of these findings is discussed.

  • In Vitro Metabolism of 2-[6-(4-Chlorophenyl)-2,2-dimethyl-7- phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] Acetic Acid (Licofelone, ML3000), an Inhibitor of Cyclooxygenase-1 and-2 and 5-Lipoxygenase
    2008
    Co-Authors: Wolfgang Albrecht, Anke Unger, Andreas K. Nussler, Stefan Laufer
    Abstract:

    pyrrolizin-5-yl] acetic acid (Licofelone) is a dual inhibitor of both cyclooxygenase isoforms and 5-lipoxygenase and under develop-ment for treatment of osteoarthritis. In conventional in vitro assays using liver microsomes and NADPH as cosubstrate, a high meta-bolic stability of Licofelone was observed. In the presence of UDP-glucuronic acid, Licofelone is rapidly converted into the corre-sponding acyl glucuronide, M1. These results are in conflict with data from clinical studies. After administration of Licofelone to humans, M1 plasma concentrations were negligibly low, whereas the exposure of the hydroxy-metabolite M2 achieved values of approximately 20 % compared with that of the parent drug. Metab-olism studies with human hepatocytes and dual-activity assays with microsomes, which allowed the simultaneous monitoring of hydroxylation and glucuronidation reactions, were performed, and the metabolic pathway of Licofelone was elucidated. After gluc