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Pancreatic enzyme inhibitor

Elissaveta Petrova, Arne Scholz, Juliane Paul, Andrea Sturz, Katja Haike, Franziska Siegel, Dominik Mumberg, Ningshu Liu
Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in de novo fatty acid synthesis, and its ACC1 isoform is overexpressed in pancreatic and various other cancers. The activity of many oncogenic signaling molecules, including WNT and Hedgehog (HH), is post-translationally modified by lipidation. Here, we report that inhibition of ACC by a small molecule inhibitor, BAY ACC002, blocked WNT3A lipidation, secretion, and signaling. In pancreatic cancer cells, where WNT and HH are key oncogenic drivers, ACC inhibition simultaneously suppressed WNT and HH signaling, and led to anti-proliferative effects...
October 13, 2016: Oncotarget
Sheldon Greer, Tieran Han, Cristina Dieguez, Nicola McLean, Rafael Saer, Isildinha Reis, Joe Levi, Victor E Marquez
Enzymatic activity from tumor and adjacent normal tissue of 200 patients involving deoxycytidine kinase (dCK), uridine/cytidine kinase (U/CK), cytidine deaminase (CD) and deoxycytidylate deaminase (dCMPD) was quantified. . Patients with brain (17), colon (24), and breast (30) tumors, 53, 67, and 73%, respectively, had an elevated T/N value (Specific Activity of tumor/ Specific Activity of normal tissue) involving dCK and dCMPD suggesting chemo therapy with 5-fluorodeoxycytidine (5-FdC) alone or in combination with thymidine plus deoxytetrahydrouridine, or with the radiosensitizer, 5-chlorodeoxycytidine (5-CldC) plus tetrahydrouridine (H4U)...
October 13, 2016: Anti-cancer Agents in Medicinal Chemistry
Jingtao Luo, Yun Hong, Xiaoan Tao, Xi Wei, Lun Zhang, Qiang Li
Unlike normal cells, cancer cells are recently identified to rely on aerobic glycolysis for energy production called the Warburg effect. Several attempts are being made to target this metabolic reprogramming pathway in treating cancers; however, the successful rate is very limited. In this study, we investigated the functional roles of fatty acid oxidation key enzyme carnitine palmitoyl transferase 1a (CPT-1a), during the metabolic programming of pancreatic ductal adenocarcinoma (PDAC) cells induced by glucose deprivation...
October 13, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Angela Corvino, Beatrice Severino, Ferdinando Fiorino, Francesco Frecentese, Elisa Magli, Elisa Perissutti, Vincenzo Santagada, Mariarosaria Bucci, Giuseppe Cirino, Geoff Kelly, Luigi Servillo, Grzegorz Popowicz, Annalisa Pastore, Giuseppe Caliendo
Hydrogen sulfide is an essential catabolite that intervenes in the pathophysiology of several diseases from hypertension to stroke, diabetes and pancreatitis. It is endogenously synthesized mainly by two pyridoxal-5'-phosphate-dependent enzymes involved in L-cysteine metabolism: cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE). Research in this field is currently impaired by the lack of pharmacological tools such as selective enzymatic inhibitors that could target specifically only one of these pathways...
October 6, 2016: Scientific Reports
Violet Kasabri, Entisar K Al-Hallaq, Yasser K Bustanji, Khalid K Abdul-Razzak, Ismail F Abaza, Fatma U Afifi
CONTEXT: Adiantum capillus-veneris L. (Adiantaceae) hypocholesterolemic activity is therapeutically praised. OBJECTIVES: Pharmacological modulation of pancreatic triacylglycerol lipase (PL) and α-amylase/α-glucosidase by A. capillus-veneris are evaluated. MATERIALS AND METHODS: Using positive controls (acarbose, orlistat, guar gum, atorvastatin, glipizide and metformin) as appropriate, crude aqueous extracts (AEs) of A. capillus-veneris aerial parts were tested via a combination of in vitro enzymatic (0...
September 23, 2016: Pharmaceutical Biology
Yongzhong Wu, Jennifer L Meitzler, Smitha Antony, Agnes Juhasz, Jiamo Lu, Guojian Jiang, Han Liu, Melinda Hollingshead, Diana C Haines, Donna Butcher, Michaela S Panter, Krishnendu Roy, James H Doroshow
Several NADPH oxidase family members, including dual oxidase 2 [DUOX2], are expressed in human tumors, particularly gastrointestinal cancers associated with long-standing chronic inflammation. We found previously that exposure of pancreatic ductal adenocarcinoma cells to the pro-inflammatory cytokine IFN-γ increased DUOX2 expression (but not other NADPH oxidases) leading to long-lived H2O2 production. To elucidate the pathophysiology of DUOX2-mediated H2O2 formation in the pancreas further, we demonstrate here that IFN-γ-treated BxPC-3 and CFPAC-1 pancreatic cancer cells (known to increase DUOX2 expression) produce significant levels of intracellular oxidants and extracellular H2O2 which correlate with concomitant up-regulation of VEGF-A and HIF-1α transcription...
September 15, 2016: Oncotarget
Barbara M Grüner, Christopher J Schulze, Dian Yang, Daisuke Ogasawara, Melissa M Dix, Zoë N Rogers, Chen-Hua Chuang, Christopher D McFarland, Shin-Heng Chiou, J Mark Brown, Benjamin F Cravatt, Matthew Bogyo, Monte M Winslow
Phenotype-based small-molecule screening is a powerful method to identify molecules that regulate cellular functions. However, such screens are generally performed in vitro under conditions that do not necessarily model complex physiological conditions or disease states. Here, we use molecular cell barcoding to enable direct in vivo phenotypic screening of small-molecule libraries. The multiplexed nature of this approach allows rapid in vivo analysis of hundreds to thousands of compounds. Using this platform, we screened >700 covalent inhibitors directed toward hydrolases for their effect on pancreatic cancer metastatic seeding...
October 2016: Nature Methods
Jing-Xuan Wu, Yi-Hua Hong, Xiao-Gai Yang
In this study, the antiproliferative effect of bis(acetylacetonato)-oxidovanadium(IV) and sodium metavanadate and the underlying mechanisms were investigated in human pancreatic cancer cell line AsPC-1. The results showed that both exhibited an antiproliferative effect through inducing G2/M cell cycle arrest and can also cause elevation of reactive oxygen species (ROS) levels in cells. Moreover, the two vanadium compounds induced the activation of both PI3K/AKT and MAPK/ERK signaling pathways dose- and time-dependently, which could be counteracted with the antioxidant N-acetylcysteine...
September 10, 2016: Journal of Biological Inorganic Chemistry: JBIC
Renata Cristina da Penha França, Caio Rodrigo Dias Assis, Juliana Ferreira Santos, Ricardo José Soares Torquato, Aparecida Sadae Tanaka, Izaura Yoshico Hirata, Diego Magno Assis, Maria Aparecida Juliano, Ronaldo Olivera Cavalli, Luiz Bezerra de Carvalho, Ranilson Souza Bezerra
A thermostable alkaline peptidase was purified from the processing waste of cobia (Rachycentron canadum) using bovine pancreatic trypsin inhibitor (BPTI) immobilized onto Sepharose. The purified enzyme had an apparent molecular mass of 24kDa by both sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrometry. Its optimal temperature and pH were 50°C and 8.5, respectively. The enzyme was thermostable until 55°C and its activity was strongly inhibited by the classic trypsin inhibitors N-ρ-tosyl-l-lysine chloromethyl ketone (TLCK) and benzamidine...
October 15, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Amira Elgogary, Qingguo Xu, Brad Poore, Jesse Alt, Sarah C Zimmermann, Liang Zhao, Jie Fu, Baiwei Chen, Shiyu Xia, Yanfei Liu, Marc Neisser, Christopher Nguyen, Ramon Lee, Joshua K Park, Juvenal Reyes, Thomas Hartung, Camilo Rojas, Rana Rais, Takashi Tsukamoto, Gregg L Semenza, Justin Hanes, Barbara S Slusher, Anne Le
Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES...
September 6, 2016: Proceedings of the National Academy of Sciences of the United States of America
Jingjing Gong, Glenn Belinsky, Usman Sagheer, Xuchen Zhang, Paul J Grippo, Chuhan Chung
An increase in autophagy characterizes pancreatic carcinogenesis, but the signals that regulate this process are incompletely understood. Because canonical Wnt/β-catenin signaling is necessary for the transition from early to advanced pancreatic intraepithelial neoplasia (PanIN) lesions, we assessed whether Wnt ligands and endogenous inhibitors of Wnt signaling modulate autophagy. In this study, canonical Wnt3a ligand induced autophagy markers and vacuoles in murine PanIN cells. Furthermore, pigment epithelium-derived factor (PEDF), a secreted glycoprotein known for its anti-tumor properties, blocked Wnt3a-directed induction of autophagy proteins...
October 14, 2016: Journal of Biological Chemistry
Friederike Remm, Wolfgang-Michael Franz, Christoph Brenner
Gliptins are accepted as a standard therapy for diabetes mellitus today. By inhibition of the enzyme dipeptidyl peptidase 4 (DPP4), gliptins prolong the GLP1-dependent insulin secretion in the pancreatic β-cells and thus support physiological blood glucose control. Various studies have now raised hope for an additional protective effect of pharmacological DPP4 inhibition in vascular diseases. Besides GLP1, especially, the inhibition of SDF1 cleavage has been shown to depict a relevant mechanism to enhance endothelial regeneration and reduce atherosclerosis progression via the SDF1-CXCR4 axis...
July 2016: European Heart Journal. Cardiovascular Pharmacotherapy
Mei-Ren Pan, Ming-Chuan Hsu, Chi-Wen Luo, Li-Tzong Chen, Yan-Shen Shan, Wen-Chun Hung
Gemcitabine (GEM) resistance is a critical issue for pancreatic cancer treatment. The involvement of epigenetic modification in GEM resistance is still unclear. We established a GEM-resistant subline PANC-1-R from the parental PANC-1 pancreatic cancer cells and found the elevation of various chromatin-modifying enzymes including G9a in GEM-resistant cells. Ectopic expression of G9a in PANC-1 cells increased GEM resistance while inactivation of G9a in PANC-1-R cells reduced it. Challenge of PANC-1 cells with GEM increased the expression of stemness markers including CD133, nestin and Lgr5 and promoted sphere forming activity suggesting chemotherapy enriched cancer cells with stem-like properties...
August 12, 2016: Oncotarget
Nobumasa Ohara, Masanori Kaneko, Kazuhiro Sato, Ryoko Maruyama, Tomoyasu Furukawa, Junta Tanaka, Kenzo Kaneko, Kyuzi Kamoi
BACKGROUND: Dipeptidyl peptidase-4 inhibitors are a class of oral hypoglycemic drugs and are used widely to treat type 2 diabetes mellitus in many countries. Adverse effects include nasopharyngitis, headache, elevated serum pancreatic enzymes, and gastrointestinal symptoms. In addition, a few cases of interstitial pneumonia associated with their use have been reported in the Japanese literature. Here we describe a patient who developed drug-induced acute lung injury shortly after the administration of the dipeptidyl peptidase-4 inhibitor vildagliptin...
2016: Journal of Medical Case Reports
Alexander Brock, Ingo Aldag, Stella Edskes, Marcus Hartmann, Torsten Herzog, Waldemar Uhl, Juergen Schnekenburger
AIM AND OBJECTIVES: Exocrine pancreatic insufficiency caused by inflammation or pancreatic tumors results in nutrient malfunction by a lack of digestive enzymes and neutralization compounds. Despite satisfactory clinical results with current enzyme therapies, a normalization of fat absorption in patients is rare. An individualized therapy is required that includes high dosage of enzymatic units, usage of enteric coating, and addition of gastric proton pump inhibitors. The key goal to improve this therapy is to identify digestive enzymes with high activity and stability in the gastrointestinal tract...
November 2016: European Journal of Gastroenterology & Hepatology
Laura E Edgington-Mitchell, Thomas Wartmann, Alicia K Fleming, Vasilena Gocheva, Wouter A van der Linden, Nimali P Withana, Martijn Verdoes, Luigi Aurelio, Daniel Edgington-Mitchell, TinaMarie Lieu, Belinda S Parker, Bim Graham, Thomas Reinheckel, John B Furness, Johanna A Joyce, Peter Storz, Walter Halangk, Matthew Bogyo, Nigel W Bunnett
Pancreatitis is an inflammatory disease of the pancreas characterized by dysregulated activity of digestive enzymes, necrosis, immune infiltration, and pain. Repeated incidence of pancreatitis is an important risk factor for pancreatic cancer. Legumain, a lysosomal cysteine protease, has been linked to inflammatory diseases such as atherosclerosis, stroke, and cancer. Until now, legumain activation has not been studied during pancreatitis. We used a fluorescently quenched activity-based probe to assess legumain activation during caerulein-induced pancreatitis in mice...
September 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Tereza Golias, Ioanna Papandreou, Ramon Sun, Bhavna Kumar, Nicole V Brown, Benjamin J Swanson, Reetesh Pai, Diego Jaitin, Quynh-Thu Le, Theodoros N Teknos, Nicholas C Denko
Tumour cells fulfil the bioenergetic and biosynthetic needs of proliferation using the available environmental metabolites. Metabolic adaptation to hypoxia causes decreased mitochondrial function and increased lactate production. This work examines the biological importance of the hypoxia-inducible inhibitory phosphorylations on the pyruvate dehydrogenase E1α subunit. Pancreatic cancer cell lines were genetically manipulated to alter the net phosphorylation of PDH E1α through reduced kinase expression or enhanced phosphatase expression...
2016: Scientific Reports
Panagiota-Yiolanda Stergiou, Athanasios Foukis, Olga A Gkini, Joseph G Bieth, Emmanuel M Papamichael
Structural and mechanistic insights were revealed for the reversible inhibition of Porcine Pancreatic Elastase (PPE); the kinetics of uninhibited and inhibited hydrolysis of substrate Suc-AAA-pNA was analyzed thoroughly. Additionally, the interactions between PPE and its inhibitor were studied by computational techniques. The uninhibited hydrolysis of Suc-AAA-pNA by PPE proceeds through a virtual transition state, involving an inferior physical and another dominating chemical step, where two stabilized reactant states precede the predominant acyl-enzyme...
August 4, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Ewa Białecka-Florjańczyk, Agata Urszula Fabiszewska, Jolanta Krzyczkowska, Alina Kuryłowicz
Lipases are enzymes that catalyse the hydrolysis of ester bonds of triglycerides ranging among biocatalysts of considerable physiological significance and industrial potential. Better understanding of the catalytic functions and achieving the possibility to control the biocatalysis process, in particular exploring some activators and inhibitors of lipases, seems to be crucial in the context of novel applications. The lipase activity is a function of interfacial composition: the enzyme can be there activated as well as denaturated or deactivated and the interface is an appropriate site for modulating lipolysis...
June 30, 2016: Mini Reviews in Medicinal Chemistry
Alice Nomura, Patricia Dauer, Vineet Gupta, Olivia McGinn, Nivedita Arora, Kaustav Majumdar, Charles Uhlrich Iii, Joseph Dalluge, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee
Chemoresistance in pancreatic cancer has been attributed to tumor-initiating cells (TICs), a minor sub-population of tumor cells. However, the mechanism of chemo-resistance in these cells is still unclear.In the current study, immunohistochemical analysis of LSL-KrasG12D; LSL-Trp53R172H;PdxCre (KPC) murine tumors indicated that hypoxic regions developed through tumor progression. This hypoxic "niche" correlated with increased CD133+ population that had an increased HIF1A activity. Consistent with this observation, CD133+ cells had increased glucose uptake and activity of glycolytic pathway enzymes compared to CD133- cells...
July 26, 2016: Oncotarget
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