HIF-PH inhibitor

INTRODUCTION: Several isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) are connected with tumorigenesis. Hypoxic tumors overexpress CA IX and XII as a consequence of HIF activation cascade, being involved in pH regulation, metabolism, metastases formation. Other isoforms (CA I, II, III, IV) were also reported to be present in some tumors. AREAS COVERED: Some CA isoforms are biomarkers for diseases progression or response to therapy. Inhibitors, antibodies, and other procedures for targeting these enzymes for the treatment of tumors/metastases are discussed...

Enarodustat (JTZ-951) is an oral hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor for the treatment of anemia with chronic kidney disease. Carcinogenicity of enarodustat was evaluated in a 26-week repeated oral dose study in Transgenic rasH2 (Tg.rasH2) mice and a 2-year repeated oral dose study in Sprague-Dawley (SD) rats. The highest dose levels were set at 6 mg/kg in the Tg.rasH2 mouse study and at 1 mg/kg in the SD rat study based on the maximum tolerated doses in the 3-month and 6-month dose-range finding studies, respectively...

Introduction The dose of roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, required to treat anemia, the hemoglobin level and the rate of hemoglobin target achievement were retrospectively investigated in non-dialyzed chronic kidney disease (CKD) patients with and without type 2 diabetes. Methods As the full analysis set, 25 subjects (10 with diabetes and 15 without diabetes) were observed over six months among 44 non-dialyzed CKD patients who received roxadustat. The target hemoglobin level was set at 110-130 g/L...

The pathologic triangle formed by chronic heart failure (HF), chronic kidney disease (CKD), and anemia carries high morbidity and mortality rates and decreases quality of life. Anemia represents a common condition in patients with advanced HF and CKD, with a total prevalence in cardiorenal syndrome (CRS) ranging from 5% to 55%. Searching for a pragmatic approach for these patients with guided and disease-specific recommendations beyond just targeted hemoglobin therapeutic behavior represents the core of research for ongoing clinical trials...

AIMS: Endothelial-mesenchymal transition (EndMT) is one of the critical factors leading to vascular remodeling in pulmonary hypertension (PH). Recent studies found that the expression of Cerebellin2 (CBLN2) is significantly increased in the lung tissue of patients with PH, suggesting that CBLN2 may be closely related to the development of PH. This study aims to investigate the role and potential mechanism of CBLN2 in the hypoxia-induced EndMT of PH rats. MATERIAL AND METHODS: Hypoxia-induced PH rat model or EndMT cell model was constructed to investigate the role of CBLN2 in the process of endothelial mesenchymal transition during PH...

Anemia is a common complication of kidney disease and the prevalence increases as the disease progresses. It worsens the quality of life of patients and increases morbidity and mortality. The current rationale for treating renal anemia is based on the use of erythropoiesis-stimulating agents, iron supplementation and, to a lesser extent, the use of transfusions. Stimulation of endogenous erythropoietin synthesis and improvement of iron availability, through inhibition of prolil-hydroxilase- hypoxia-inducible factor (PH-HIF), represents a new oral alternative for renal anemia treatment...

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the standard treatment for patients with renal anemia to increase hemoglobin (Hb) levels and reduce the need for blood transfusions. However, treatments targeting high Hb levels require high doses of ESAs administered intravenously, which is associated with an elevated risk of adverse cardiovascular events. Furthermore, there have been some problems such as hemoglobin variability and low achievement of target hemoglobin due to the shorter half-lives of ESAs...

The term cancer refers to a plethora of diseases characterized by the development of abnormal cells that divide uncontrollably and can infiltrate further proximal or distal body tissues. Each type of cancer can be defined by aggressiveness, localization, metabolism, and response to available treatments. Among the most common hallmarks of cancer is a more acidic intracellular microenvironment. Offset pH values are due to an excess of lactate and an increased hypoxia-inducible factor (HIF) expression, which leads to a hypoxic state and a metabolic shift towards glycolysis to produce adenosine-5'-triphosphate (ATP) necessary for cellular metabolism...

Overexpression of two carbonic anhydrase (CA) isoforms, CA IX and XII, in several hypoxic solid tumors provides an extracellular hypoxic microenvironment, interferes with extra- and intracellular pH regulation, thus favoring hypoxic tumor cell survival, proliferation and metastasis. In the current study, a selective inhibitor for human CA isoforms IX and XII (isatin-bearing sulfonamide, WEG-104), was incorporated into nanosized spherical niosomes at high encapsulation efficiency to allow for an enhanced and sustained antitumor activity...

Increased mitochondrial reactive oxygen species (mROS) and glycolysis have been established in pulmonary hypertension (PH). However, the effect of elevated mROS on glycolytic shift and how increased glycolysis promotes hypoxic pulmonary artery smooth muscle cell (PASMC) proliferation and vascular remodeling remain elusive. Here, we reported that hypoxia-induced mROS inhibit HIF-1α hydroxylation and further trigger PASMC glycolytic switch through the upregulated HIF-1α/PDK1&PDK2/p-PDH-E1α axis, which facilitates lactate accumulation and histone lactylation...

No abstract text is available yet for this article.

TP0463518, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor, is reportedly excreted predominantly through urinary excretion in an unchanged form in humans, with partial biliary excretion also possible. However, the clearance mechanisms remain unclear. The aim of this study was to investigate the clearance mechanisms in humans and to assess species differences in the excretion routes.TP0463518 was not metabolized in rat, dog, or human hepatocytes. TP0463518 is a substrate for human BCRP, OATP1B1, OATP1B3, and OAT3, suggesting that renal uptake by OAT3 is probably the predominant clearance route, with hepatic uptake by OATP1B1 and OATP1B3 contributing partially to clearance in humans...

BACKGROUND: Autophagy plays an important role in the pathogenesis of pulmonary hypertension (PH). ROC-325 is a novel small molecule lysosomal autophagy inhibitor that has more potent anticancer activity than the antimalarial drug hydroxychloroquine, the latter has been prevalently used to inhibit autophagy. Here, we sought to determine the therapeutic benefit and mechanism of action of ROC-325 in experimental PH models. METHODS AND RESULTS: Hemodynamics, echocardiography, and histology measurement showed that ROC-325 treatment prevented the development of PH, right ventricular hypertrophy, fibrosis, dysfunction, and vascular remodeling after monocrotaline and Sugen5416/hypoxia administration...

Multidrug resistance (MDR) is the main cause of clinical chemotherapy failure, and new strategies to overcome MDR are needed. We report multi-responsive silk fibroin nanoparticles (SFNs) co-loaded with the chemotherapeutic drug doxorubicin (DOX) and PX478 (a hypoxia-inducible factor inhibitor), which was functionalized with folic acid (FA). This combination could actively target tumor cells and respond to the release of PX478, inhibit the hypoxia-inducible factor (HIF) gene and its related downstream drug-resistant target genes...

Acetylation can be regulated by histone deacetylases (HDACs) and histone acetyltransferases (HATs), and the imbalance between HDACs and HATs can lead to cancers. Trichostatin A (TSA), as one of the typical HDAC inhibitors (HDACis), may regulate the acetylation level and thus prevent the proliferation of cancer cells, in which the metabolic change of glycolysis is involved. However, the dynamic process of glycolysis has not yet been explored, and the mechanism is still elusive. In this work, we constructed GFP-actin-HeLa cells to observe the dynamic change of glycolysis in situ and found that the GFP fluorescence enhanced significantly after TSA treatment, which was consistent with the change of pH in the cells (pHi ) depending on the change of lactate originated from glycolysis...

Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors might improve renal anemia maintaining fewer cardiovascular complications. However, its safety and efficacy, as well as its impact on inflammatory biomarkers, in heart failure patients remain unknown. We initiated HIF-PH inhibitors in 13 patients with chronic heart failure and renal anemia (median age 77 years, median estimated glomerular filtration rate 24.9 mL/min/1.73m2 ) between September 2021 and February 2022. There were no drug-related complications, except for a patient who had a headache and hot flash, resulting in discontinuation of HIF-PH inhibitor at 3 months...

BACKGROUND: Anemia is common in heart failure (HF) patients with chronic kidney disease (CKD) and is associated with worse outcomes. Iron supplementation improves symptoms and is associated with reduced risk of hospitalization for HF in iron-deficiency HF patients. However, iron deficiency is present in <30% of anemic HF patients. Erythropoiesis stimulating agents (ESAs) improve symptoms but are associated with increased risk of thromboembolic events in anemic HF patients with CKD...

Oxygen is essential for living organisms. Molecular oxygen binds to hemoglobin and is delivered to every organ in the body. In several cardiovascular diseases or anemia, local oxygen tension drops below its physiological level and tissue hypoxia develops. In such conditions, the expression of hypoxia-responsive genes increases to alleviate the respective condition. The hypoxia-responsive genes include the genes coding erythropoietin (EPO), vascular endothelial growth factor-A, and glycolytic enzymes. Hypoxia-inducible factor (HIF)-1α, HIF-2α, and HIF-3α are transcription factors that regulate the hypoxia-responsive genes...

The transcription factors hypoxia-inducible factor-1α and -2α (HIF-1α/2α) are the major regulators of the cellular response to hypoxia and play a key role in renal fibrosis associated with acute and chronic kidney disease. Jumonji domain-containing 1a (JMJD1A), a histone H3 lysine 9 (H3K9) demethylase, is reported to be an important target gene of HIF-α. However, whether JMJD1A and H3K9 methylation status play a role in renal fibrosis is unclear. Here, we investigated the involvement of HIF-α, JMJD1A, and monomethylated/dimethylated H3K9 (H3K9me1/H3K9me2) levels in unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice...

No abstract text is available yet for this article.