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HIF-PH inhibitor

M Kery, N Oravcova, S Radenkovic, F Iuliano, J Tomaskova, T Golias
Pyruvate dehydrogenase kinase 1 (PDHK1) and carbonic anhydrase IX (CAIX) are two of the most hypoxia-inducing proteins in tumors. PDHK1 is involved in glucose metabolism and CAIX in pH regulation, and both appear necessary for model tumor growth. Their hypoxia induces their expression and enzymatic activity, and high expression level in human tumors predicts poor patient outcome. This paper targets these two proteins both pharmacologically and genetically and in vitro and in vivo because they can lead to decreased cancer cell survival and significantly reduce model tumor growth...
August 9, 2018: Neoplasma
Claudiu T Supuran
Hypoxic tumors overexpress two carbonic anhydrases (CA, EC, CA IX and XII, involved in complex processes connected to tumorigenesis (pH regulation, metabolism, invasion, and dissemination of the tumor). The biochemical rationale behind these processes is orchestrated by the transcription factor hypoxia inducible factor 1 (HIF-1). Areas covered: CA IX and XII have been validated as antitumor/antimetastatic drug targets and may be used for imaging hypoxic tumors. Many CA inhibitors (CAIs) belonging to the sulfonamide, coumarin and sulfocoumarin classes selectively inhibit these two isoforms...
December 2018: Expert Opinion on Investigational Drugs
Derek P Logsdon, Fenil Shah, Fabrizio Carta, Claudiu T Supuran, Malgorzata Kamocka, Max H Jacobsen, George E Sandusky, Mark R Kelley, Melissa L Fishel
Pancreatic ductal adenocarcinoma (PDAC) has reactive stroma that promotes tumor signaling, fibrosis, inflammation, and hypoxia, which activates HIF-1α to increase tumor cell metastasis and therapeutic resistance. Carbonic anhydrase IX (CA9) stabilizes intracellular pH following induction by HIF-1α. Redox effector factor-1 (APE1/Ref-1) is a multifunctional protein with redox signaling activity that converts certain oxidized transcription factors to a reduced state, enabling them to upregulate tumor-promoting genes...
September 13, 2018: Scientific Reports
Yamhilette Licon-Munoz, Colleen A Fordyce, Summer Raines Hayek, Karlett J Parra
Prostate Cancer (PCa) is the most commonly diagnosed cancer and the third leading cause of death for men in the United States. Suppression of androgen receptor (AR) expression is a desirable mechanism to manage PCa. Our studies showed that AR expression was reduced in LAPC4 and LNCaP PCa cell lines treated with nanomolar concentrations of the V-ATPase inhibitor concanamycin A (CCA). This treatment decreased PSA mRNA levels, indicative of reduced AR activity. V-ATPase-dependent repression of AR expression was linked to defective endo-lysosomal pH regulation and reduced AR expression at the transcriptional level...
June 22, 2018: Oncotarget
Takeshi Hasegawa, Fumihiko Koiwa, Tadao Akizawa
Renal anemia is a serious and common complication in hemodialysis (HD) patients. The introduction of erythropoiesis-stimulating agents (ESAs) has dramatically improved hemoglobin levels and outcomes. Several interventional studies reported that excessive correction of anemia and the massive use of ESA can trigger cardiovascular disease (CVD), and consequently may worsen the prognosis of patients undergoing HD. Therefore, it has been widely recognized that large doses of ESA should be used with caution. An effective use of iron preparations is required to yield the optimal effect of ESA...
November 2018: Seminars in Dialysis
Astrid Drenckhan, Morton Freytag, Claudiu T Supuran, Guido Sauter, Jakob R Izbicki, Stephanie J Gros
The hypoxic tumour microenvironment of solid tumours represents an important starting point for modulating progression and metastatic spread. Carbonic anhydrase IX (CAIX) is a known HIF-1α-dependent key player in maintaining cell pH conditions under hypoxia. We show that CAIX is strongly expressed in esophageal carcinoma tissues. We hypothesize that a moderate CAIX expression facilitates metastases and thereby worsens prognosis. Selective inhibition of CAIX by specific CAIX inhibitors and a CAIX knockdown effectively inhibit proliferation and migration in vitro...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
M Böttcher, S Lentini, E R Arens, A Kaiser, D van der Mey, U Thuss, D Kubitza, G Wensing
AIMS: Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers. METHODS: This was a single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study...
July 2018: British Journal of Clinical Pharmacology
Hartmut Beck, Mario Jeske, Kai Thede, Friederike Stoll, Ingo Flamme, Metin Akbaba, Jens-Kerim Ergüden, Gunter Karig, Jörg Keldenich, Felix Oehme, Hans-Christian Militzer, Ingo V Hartung, Uwe Thuss
Small-molecule inhibitors of hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) are currently under clinical development as novel treatment options for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased erythropoietin (EPO) expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, structure-activity relationship (SAR), and proposed binding mode of novel 2,4-diheteroaryl-1,2-dihydro-3H-pyrazol-3-ones as orally bioavailable HIF-PH inhibitors for the treatment of anemia...
May 23, 2018: ChemMedChem
James Beck, Carroll Henschel, James Chou, Al Lin, Ughetta Del Balzo
The carcinogenic potential of roxadustat (FG-4592), a novel orally active, heterocyclic small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzymes in clinical development for treatment of anemia, was evaluated in CD-1 mice and Sprague Dawley rats. Inhibition of HIF-PH by roxadustat leads to a rapid increase in cytoplasmic HIF-α concentrations, followed by translocation of HIF-α to the nucleus and upregulation of HIF-responsive genes, including erythropoietin. Roxadustat was dosed by oral gavage 3 times weekly (TIW) for up to 104 weeks in mice at 0, 15, 30, and 60 mg/kg and in rats at 0, 2...
November 2017: International Journal of Toxicology
Ingo Flamme, Peter Ellinghaus, Diana Urrego, Thilo Krüger
Plasma levels of FGF23 are increased in patients with chronic kidney disease. Beside its role in phosphate homeostasis, iron deficiency and anemia are associated with increased FGF23 plasma levels. Recently, FGF23 plasma levels were shown to be increased in mice after treatment with hypoxia inducible factor-proline hydroxylase (HIF-PH) inhibitors which are strong inducers of erythropoietin and erythropoiesis and are known to modulate iron uptake and availability. Therefore we investigated a potential context between expression of FGF23 and stimulation of erythropoiesis using a HIF-PH inhibitor and erythropoietin in rats...
2017: PloS One
Santhosh Kumar Ghadge, Moritz Messner, Thi Van Pham, Maximilian Doppelhammer, Andreas Petry, Agnes Görlach, Britta Husse, Wolfgang-Michael Franz, Marc-Michael Zaruba
SDF-1/CXCR4 activation facilitates myocardial repair. Therefore, we aimed to activate the HIF-1α target genes SDF-1 and CXCR4 by dimethyloxalylglycine (DMOG)-induced prolyl-hydroxylase (PH) inhibition to augment CXCR4+ cell recruitment and myocardial repair. SDF-1 and CXCR4 expression was analyzed under normoxia and ischemia ± DMOG utilizing SDF-1-EGFP and CXCR4-EGFP reporter mice. In bone marrow and heart, CXCR4-EGFP was predominantly expressed in CD45+/CD11b+ leukocytes which significantly increased after myocardial ischemia...
August 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Saveg Yadav, Shrish Kumar Pandey, Ajay Kumar, Praveen Kumar Kujur, Rana Pratap Singh, Sukh Mahendra Singh
3-Bromopyruvate (3-BP), brominated derivative of pyruvate, possesses strong antitumor potential, owing to its ability to inhibit multiple target molecules crucial for survival of neoplastic cells. Although, 3-BP displays cytotoxicity against a wide variety of tumors, there is no report with respect to malignancies of thymic origin. Therefore, we investigated its antineoplastic action in vitro against tumor cells of a murine transplantable lymphoma of thymoma origin, designated as Dalton's lymphoma (DL). 3-BP treatment of tumor cells inhibited metabolism and survival with augmented induction of apoptosis and necrosis...
May 25, 2017: Chemico-biological Interactions
Nupur Gupta, Jay B Wish
Erythropoiesis-stimulating agents (ESAs) increase hemoglobin levels, reduce transfusion requirements, and have been the standard of treatment for anemia in patients with chronic kidney disease (CKD) since 1989. Many safety concerns have emerged regarding the use of ESAs, including an increased occurrence of cardiovascular events and vascular access thrombosis. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitors are a new class of agents for the treatment of anemia in CKD. These agents work by stabilizing the HIF complex and stimulating endogenous erythropoietin production even in patients with end-stage kidney disease...
June 2017: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
Claudiu T Supuran
Carbonic anhydrase IX (CA IX) is an enzyme overexpressed in many hypoxic tumors as a consequence of hypoxia inducible factor 1α (HIF-1α) transcription factor cascade. CA IX is a highly active catalyst for the conversion of CO2 to bicarbonate and protons, being involved in pH regulation, but also contributes to the acquisition of metastasic phenotypes and to chemoresistance with some widely used anticancer drugs. CA IX inhibition with small molecules or antibodies has profound antitumor/antimetastatic effects, and also depletes the number of cancer stem cells within the hypoxic niche, all factors crucial for new generation anticancer agents...
August 30, 2016: Expert Opinion on Therapeutic Patents
Daniel Abebayehu, Andrew J Spence, Amina Abdul Qayum, Marcela T Taruselli, Jamie J A McLeod, Heather L Caslin, Alena P Chumanevich, Elizabeth Motunrayo Kolawole, Anuya Paranjape, Bianca Baker, Victor S Ndaw, Brian O Barnstein, Carole A Oskeritzian, Scott A Sell, John J Ryan
Lactic acid (LA) is present in tumors, asthma, and wound healing, environments with elevated IL-33 and mast cell infiltration. Although IL-33 is a potent mast cell activator, how LA affects IL-33-mediated mast cell function is unknown. To investigate this, mouse bone marrow-derived mast cells were cultured with or without LA and activated with IL-33. LA reduced IL-33-mediated cytokine and chemokine production. Using inhibitors for monocarboxylate transporters (MCT) or replacing LA with sodium lactate revealed that LA effects are MCT-1- and pH-dependent...
October 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Sergiy M Nadtochiy, Xenia Schafer, Dragony Fu, Keith Nehrke, Joshua Munger, Paul S Brookes
2-Hydroxyglutarate (2-HG) is an important epigenetic regulator, with potential roles in cancer and stem cell biology. The d-(R)-enantiomer (d-2-HG) is an oncometabolite generated from α-ketoglutarate (α-KG) by mutant isocitrate dehydrogenase, whereas l-(S)-2-HG is generated by lactate dehydrogenase and malate dehydrogenase in response to hypoxia. Because acidic pH is a common feature of hypoxia, as well as tumor and stem cell microenvironments, we hypothesized that pH may regulate cellular 2-HG levels. Herein we report that cytosolic acidification under normoxia moderately elevated 2-HG in cells, and boosting endogenous substrate α-KG levels further stimulated this elevation...
September 16, 2016: Journal of Biological Chemistry
Andrew C Selfridge, Miguel A S Cavadas, Carsten C Scholz, Eric L Campbell, Lynn C Welch, Emilia Lecuona, Sean P Colgan, Kim E Barrett, Peter H S Sporn, Jacob I Sznajder, Eoin P Cummins, Cormac T Taylor
Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway...
May 27, 2016: Journal of Biological Chemistry
Peng Wang, Ling Li, Zhenxiang Zhang, Quancheng Kan, Feng Gao, Suyan Chen
Hypoxia causes injury to the central nervous system during stroke and has significant effects on pH homeostasis. Na+/H+ exchanger isoform 1 (NHE1) is important in the mechanisms of hypoxia and intracellular pH (pHi) homeostasis. As a well-established hypoxia-mimetic agent, CoCl2 stabilizes and increases the expression of hypoxia inducible factor‑1α (HIF-1α), which regulates several genes involved in pH balance, including NHE1. However, it is not fully understood whether NHE1 is activated in astrocytes under CoCl2 treatment...
May 2016: Molecular Medicine Reports
Poorella Lingeshwar, Gurpreet Kaur, Neetu Singh, Seema Singh, Akanksha Mishra, Shubha Shukla, Rachumallu Ramakrishna, Tulsankar Sachin Laxman, Rabi Sankar Bhatta, Hefazat H Siddiqui, Kashif Hanif
Increased sympathetic nervous system (SNS) activity is associated with cardiovascular diseases but its role has not been completely explored in pulmonary hypertension (PH). Increased SNS activity is distinguished by elevated level of norepinephrine (NE) and activity of γ-Amino butyric acid Transminase (GABA-T) which degrades GABA, an inhibitory neurotransmitter within the central and peripheral nervous system. Therefore, we hypothesized that GABA-T may contribute in pathophysiology of PH by modulating level of GABA and NE...
February 2016: Pulmonary Pharmacology & Therapeutics
Caryn S Gonsalves, Chen Li, Punam Malik, Stanley M Tahara, Vijay K Kalra
Endothelin-1 (ET-1) and plasminogen activator inhibitor-1 (PAI-1) play important roles in pulmonary hypertension (PH) in sickle cell disease (SCD). Our previous studies show higher levels of placenta growth factor (PlGF) in SCD correlate with increased plasma levels of ET-1, PAI-1, and other physiological markers of PH. PlGF-mediated ET-1 and PAI-1 expression occurs via activation of hypoxia-inducible factor-1α (HIF-1α). However, relatively little is understood regarding post-transcriptional regulation of PlGF-mediated expression of ET-1 and PAI-1...
October 12, 2015: Bioscience Reports
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