Gram‐Scale Solution‐Phase Synthesis of Selective Sodium Bicarbonate Co‐transport Inhibitor S0859: in vitro Efficacy Studies in Breast Cancer Cells

Larsen, Ann M.; Krogsgaard‐Larsen, Niels; Lauritzen, Gitte; Olesen, Christina W.; Hansen, Steen Honoré; Boedtkjer, Ebbe; Pedersen, Stine Falsig; Bunch, Lennart

doi:10.1002/cmdc.201200335

Cited by 28 publications

(27 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Like most pharmacologic inhibitors, recent data identified possible off-target effects of S0859 including inhibition of lactate transporters ectopically expressed in oocytes (31). Given the similarities in responses between S0859 and the NDBT knockdown studies, it is likely that the NDBT are the major targets here as described previously (7,29,30).…”

Section: Discussionmentioning

confidence: 71%

“…This small molecule inhibitor blocks the bulk of acid extrusion carried by sodium-driven bicarbonate transport (7,29,30), but other proteins have been shown to be sensitive to S0859 including lactate transporters ectopically expressed in oocytes (31). We used S0859 to explore the role of sodium driven bicarbonate transporters on 3D spheroid growth and intracellular pH regulation.…”

Section: Oh àmentioning

confidence: 99%

“…S0859 was produced by Peter Seden (University of Oxford, Oxford, United Kingdom) as described previously (30) or from Sigma-Aldrich.…”

Section: Chemicalsmentioning

confidence: 99%

See 2 more Smart Citations

Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth

et al. 2016

View full text Add to dashboard Cite

Tumor hypoxia is associated clinically with therapeutic resistance and poor patient outcomes. One feature of tumor hypoxia is activated expression of carbonic anhydrase IX (CA9), a regulator of pH and tumor growth. In this study, we investigated the hypothesis that impeding the reuptake of bicarbonate produced extracellularly by CA9 could exacerbate the intracellular acidity produced by hypoxic conditions, perhaps compromising cell growth and viability as a result. In 8 of 10 cancer cell lines, we found that hypoxia induced the expression of at least one bicarbonate transporter. The most robust and frequent inductions were of the sodium-driven bicarbonate transporters SLC4A4 and SLC4A9, which rely upon both HIF1a and HIF2a activity for their expression. In cancer cell spheroids, SLC4A4 or SLC4A9 disruption by either genetic or pharmaceutical approaches acidified intracellular pH and reduced cell growth. Furthermore, treatment of spheroids with S0859, a small-molecule inhibitor of sodium-driven bicarbonate transporters, increased apoptosis in the cell lines tested. Finally, RNAi-mediated attenuation of SLC4A9 increased apoptosis in MDA-MB-231 breast cancer spheroids and dramatically reduced growth of MDA-MB-231 breast tumors or U87 gliomas in murine xenografts. Our findings suggest that disrupting pH homeostasis by blocking bicarbonate import might broadly relieve the common resistance of hypoxic tumors to anticancer therapy. Cancer Res; 76(13); 3744-55. Ó2016 AACR.

show abstract

Section: Discussionmentioning

confidence: 71%

Section: Oh àmentioning

confidence: 99%

See 1 more Smart Citation

Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth

et al. 2016

View full text Add to dashboard Cite

show abstract

“…A synthesis protocol based on commercially available compounds has been developed by Larsen and co-workers and is provided in Ref. 545. 31 Bachmann et al cite unpublished observations from Aventis Laboratories that S0859 blocks NBCe1 with a K i ϳ6 M, but does not block NBC2/3 (i.e., NDCBE) as expressed in CHO cells.…”

Section: Ncbt Inhibitionmentioning

confidence: 99%

The Divergence, Actions, Roles, and Relatives of Sodium-Coupled Bicarbonate Transporters

Parker

Boron

2013

Physiological Reviews

248

262

View full text Add to dashboard Cite

The mammalian Slc4 (Solute carrier 4) family of transporters is a functionally diverse group of 10 multi-spanning membrane proteins that includes three Cl-HCO3 exchangers (AE1-3), five Na(+)-coupled HCO3(-) transporters (NCBTs), and two other unusual members (AE4, BTR1). In this review, we mainly focus on the five mammalian NCBTs-NBCe1, NBCe2, NBCn1, NDCBE, and NBCn2. Each plays a specialized role in maintaining intracellular pH and, by contributing to the movement of HCO3(-) across epithelia, in maintaining whole-body pH and otherwise contributing to epithelial transport. Disruptions involving NCBT genes are linked to blindness, deafness, proximal renal tubular acidosis, mental retardation, and epilepsy. We also review AE1-3, AE4, and BTR1, addressing their relevance to the study of NCBTs. This review draws together recent advances in our understanding of the phylogenetic origins and physiological relevance of NCBTs and their progenitors. Underlying these advances is progress in such diverse disciplines as physiology, molecular biology, genetics, immunocytochemistry, proteomics, and structural biology. This review highlights the key similarities and differences between individual NCBTs and the genes that encode them and also clarifies the sometimes confusing NCBT nomenclature.

show abstract

“…Thus, its effect is specific to NCBTs, at least in ventricular cardiomyocytes. More recent studies also show that S0859 inhibits NBCn1 activity in the human breast cancer cell line MCF-7 (175) whereas surprisingly S0859 had no effect on Na,HCO 3 -cotransport activity in isolated arteries or slices of murine breast tumors (175). NBCn1 is responsible for Na,HCO 3 -cotransport activity in both of these tissues and differences in transporter isoform, therefore, does not appear to explain the difference.…”

Section: The Postcloning Eramentioning

confidence: 98%

Cation‐Coupled Bicarbonate Transporters

Aalkjær

Boedtkjer

Choi

et al. 2014

Comprehensive Physiology

Self Cite

View full text Add to dashboard Cite

Cation-coupled HCO3− transport was initially identified in the mid-1970s when pioneering studies showed that acid extrusion from cells is stimulated by CO2/HCO3− and associated with Na+ and Cl− movement. The first Na+-coupled bicarbonate transporter (NCBT) was expression-cloned in the late 1990s. There are currently five mammalian NCBTs in the SLC4-family: the electrogenic Na,HCO3-cotransporters NBCe1 and NBCe2 (SLC4A4 and SLC4A5 gene products); the electroneutral Na,HCO3-cotransporter NBCn1 (SLC4A7 gene product); the Na+-driven Cl,HCO3-exchanger NDCBE (SLC4A8 gene product); and NBCn2/NCBE (SLC4A10 gene product), which has been characterized as an electroneutral Na,HCO3-cotransporter or a Na+-driven Cl,HCO3-exchanger. Despite the similarity in amino acid sequence and predicted structure among the NCBTs of the SLC4-family, they exhibit distinct differences in ion dependency, transport function, pharmacological properties, and interactions with other proteins. In epithelia, NCBTs are involved in transcellular movement of acid-base equivalents and intracellular pH control. In nonepithelial tissues, NCBTs contribute to intracellular pH regulation; and hence, they are crucial for diverse tissue functions including neuronal discharge, sensory neuron development, performance of the heart, and vascular tone regulation. The function and expression levels of the NCBTs are generally sensitive to intracellular and systemic pH. Animal models have revealed pathophysiological roles of the transporters in disease states including metabolic acidosis, hypertension, visual defects, and epileptic seizures. Studies are being conducted to understand the physiological consequences of genetic polymorphisms in the SLC4-members, which are associated with cancer, hypertension, and drug addiction. Here, we describe the current knowledge regarding the function, structure, and regulation of the mammalian cation-coupled HCO3− transporters of the SLC4-family.

show abstract

Gram‐Scale Solution‐Phase Synthesis of Selective Sodium Bicarbonate Co‐transport Inhibitor S0859: in vitro Efficacy Studies in Breast Cancer Cells

Cited by 28 publications

References 32 publications

Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth

Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth

The Divergence, Actions, Roles, and Relatives of Sodium-Coupled Bicarbonate Transporters

Cation‐Coupled Bicarbonate Transporters

Contact Info

Product

Resources

About