An overview of inhibitors of Na+/H+ exchanger

Masereel, Bernard; Pochet, Lionel; Laeckmann, Didier

doi:10.1016/s0223-5234(03)00100-4

Cited by 391 publications

(353 citation statements)

References 52 publications

Supporting

Mentioning

327

Contrasting

Unclassified

Order By: Relevance

“…NHE1 is involved in tumorigenesis, as deletion of this protein drastically reduces tumour growth 82 . The same effects have been observed using pharmacological inhibitors 6,83 such as amiloride or cariporide 84 (compound 23 and 24; FIG. 4).…”

Section: Inhibiting Other Hcosupporting

confidence: 61%

See 1 more Smart Citation

Interfering with pH regulation in tumours as a therapeutic strategy

Neri¹,

Supuran

2011

Nat Rev Drug Discov

1,352

1,269

View full text Add to dashboard Cite

The growth of solid tumours is characterized not only by the uncontrolled proliferation of cancer cells but also by changes in the tumour environment that support the growth of the neoplastic mass and the metastatic spread of cancer cells to distant sites 1 . The formation of new blood vessels from pre-existing ones (angiogenesis) provides oxygen and nutrients to the tumour, which are essential for tumour growth 2 . A complex dynamic interplay exists between the expanding neoplastic mass and the tumour environment, which is affected by the metabolic requirements of cancer cells and by their products, such as secreted proteins (for example, extracellular matrix components and proteases) and metabolites.Upregulated glucose metabolism is a hallmark of invasive cancers 3 . In normal cells glucose is converted to glucose-6-phosphate and subsequently to pyruvate, which is then oxidized in the mitochondria to carbon dioxide and water; this releases 38 moles of ATP per mole of glucose 3 . However, inadequate oxygen delivery to some regions of tumours leads to hypoxia, which restricts oxidative phosphorylation. As a consequence, hypoxic tumour cells shift their metabolism towards glycolysis so that the pyruvate generated in the first step of the process is reduced to lactate, generating only 2 moles of ATP per mole of glucose. This is a less energy-efficient process but it does not depend on oxygen. Furthermore, glycolysis often persists even after reoxygenation because the obtained metabolic intermediates (that is, lactate and pyruvate) can be used for the biosynthesis of amino acids, nucleotides and lipids, thus providing a selective advantage to proliferating tumour cells. This explains Warburg's observation of high glucose consumption and high lactate production in tumour tissues 3-5 (known as the Warburg effect).Oncogenic metabolism also generates an excess of protons and carbon dioxide, which are kept in equilibrium with carbonic acid by the enzyme carbonic anhydrase 3-9 . Thus, increased glucose metabolism in tumour cells leads to enhanced acidification of the extracellular milieu, which is frequently accompanied by various levels of hypoxia. This phenotype confers a substantial Darwinian growth advantage to tumour cells over normal cells, which undergo apoptosis in response to such an acidic extracellular environment 3 .Tumour cells have evolved various mechanisms to cope with the acidic and hypoxic stress mentioned above. They eliminate acidic catabolites by ion transporters and pumps to preserve a slightly alkaline intracellular pH (pH i ), which is optimal for cell proliferation and tumour survival 3-10 . Acid export leads to a reduction in the extracellular pH (pH e ) to values as low as 6.0 (the usual pH e in tumours is in the range of 6.5-7.0) 3 , which is a salient feature of the tumour microenvironment 3-9 . As well as triggering the overexpression of many proteins involved in glucose metabolism -such as the glucose transporter GLUT1 (also known as SLC2A1) and pH-regulating proteins such as carbonic anhyd...

show abstract

Section: Inhibiting Other Hcosupporting

confidence: 61%

“…4). There are numerous NHE1 inhibitors that are structurally related to amiloride and cariporide, all of them possessing the pyrazine-acylguanidine scaffold that is present in amiloride along with various other substituents to the pyrazine ring 84 .…”

Section: Inhibiting Other Hcomentioning

confidence: 99%

Interfering with pH regulation in tumours as a therapeutic strategy

Neri¹,

Supuran

2011

Nat Rev Drug Discov

1,352

1,269

View full text Add to dashboard Cite

show abstract

“…The mature plasmalemmal NHE1 protein is both N-and O-glycosylated, although glycosylation is not required for transport function [61,33]. NHE1 is highly sensitive to amiloride, the first NHE1 inhibitor identified [137,103]. Subsequently, more selective and potent inhibitors have been developed including lipophilic amiloride derivatives (e.g.…”

Section: Slc9a1-nhe1mentioning

confidence: 99%

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Fuster

Alexander

2013

Pflugers Arch - Eur J Physiol

137

122

View full text Add to dashboard Cite

The SLC9 gene family encodes Na + /H + exchangers (NHEs). These transmembrane proteins transport ions across lipid bilayers in a diverse array of species from prokaryotes to eukaryotes, including plants, fungi and animals. They utilize the electrochemical gradient of one ion to transport another ion against its electrochemical gradient. Currently, 13 evolutionarily conserved NHE isoforms are known in mammals [46,22,128]. The SLC9 gene family (solute carrier classification of transporters:www.bioparadigms.org) is divided into three subgroups [46]. The SLC9A subgroup encompasses plasmalemmal isoforms NHE1-5 (SLC9A1-5) and the predominantly intracellular isoforms NHE6-9 (SLC9A6-9). The SLC9B subgroup consists of two recently cloned isoforms, NHA1 and NHA2 (SLC9B1 and SLC9B2, respectively). The SLC9C subgroup consist of a sperm specific plasmalemmal NHE (SLC9C1) and a putative NHE, SLC9C2, for which there is currently no functional data [46].NHEs participate in the regulation of cytosolic and organellar pH as well as cell volume. In the intestine and kidney, NHEs are critical for transepithelial movement of Na + and HCO 3 -and thus for whole body volume and acid-base homeostasis [46]. Mutations in the NHE6 or NHE9 genes cause neurological disease in humans and are currently the only NHEs directly linked to human disease.However, it is becoming increasingly apparent that members of this gene family contribute to the pathophysiology of multiple human diseases.

show abstract

“…The experiments were performed in the presence or absence of 20 μM HMA and 20 μM EIPA, two NHE inhibitors 23 , to evaluate the possible involvement of NHA-oc/NHA2. Permeabilized cells were then loaded with the pH-sensitive dye loaded 2′, 7′-bis(2-carboxyethyl)-5(6)carboxyfluorescein (BCECF-450/490-nm) (Molecular Probes) for 10 min and the cells were then washed and post-incubated.…”

Section: Intramitachondrial (H + ) Measurementsmentioning

confidence: 99%

“…Transfectected as well as control untransfected PS120 cells were then permeabilized for 10 min in'intracellular-like' buffer containing 10mM NaCl (see METHODS) and loaded with the pH-sensitive dye BCECF, whose fluorescent excitation ratio (450/490 nm) is pH-dependent. To test for CPA activity, mitochondrial fluorescence was monitored after abrupt removal of Na + , in the presence and absence of HMA and EIPA, two wide range NHE inhibitors 23 . Na + removal from the medium induced an immediate increase in mitochondrial H + in pNHE-oc/V5-6× His-transfected cells, which was visualized as a change in the fluorescence at 488 nm (Compare 6C and 6D).…”

Section: Nha-oc/nha2 Mediates Na + -Dependent Changes In Mitochondriamentioning

confidence: 99%

NHA-oc/NHA2: A mitochondrial cation–proton antiporter selectively expressed in osteoclasts

Battaglino¹,

Pham²,

Morse

et al. 2008

Bone

View full text Add to dashboard Cite

Bone resorption is regulated by a complex system of hormones and cytokines that cause osteoblasts/stromal cells and lymphocytes to produce factors including RANKL, that ultimately result in the differentiation and activation of osteoclasts, the bone resorbing cells.We used a microarray approach to identify genes upregulated in RANKL-stimulated osteoclastprecursor cells. Osteoclast expression was confirmed by multiple tissue Northern and in situ hybridization analysis. Gene function studies were carried out by siRNA analysis.We identified a novel gene, which we termed nha-oc/NHA2, which is strongly upregulated during RANKL-induced osteoclast differentiation in vitro and in vivo. nha-oc/NHA2 encodes a novel cation/proton antiporter (CPA), and is the mouse orthologue of a human gene identified in a database search: HsNHA2. nha-oc/NHA2 is selectively expressed in osteoclasts. NHA-oc/NHA2 protein localizes to the mitochondria, where it mediates Na + -dependent changes in mitochondrial pH and Na + Acetate induced-mitochondrial passive swelling. RNA silencing of nha-oc/nha2 reduces osteoclast differentiation and resorption, suggesting a role for NHA-oc/NHA2 in these processes.nha-oc/NHA2 therefore is a novel member of the CPA family, and is the first mitochondrial NHA characterized to date. nha-oc/NHA2 is also unique in that it is the first eukaryotic and tissue specific CPA2 characterized to date. NHA-oc/NHA2 displays the expected activities of a bona fide CPA and plays a key role(s) in normal osteoclast differentiation and function.

show abstract

An overview of inhibitors of Na+/H+ exchanger

Cited by 391 publications

References 52 publications

Interfering with pH regulation in tumours as a therapeutic strategy

Interfering with pH regulation in tumours as a therapeutic strategy

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

NHA-oc/NHA2: A mitochondrial cation–proton antiporter selectively expressed in osteoclasts

Contact Info

Product

Resources

About