Na<sup>+</sup>/H<sup>+</sup> exchange subtype 1 inhibition during extracellular acidification and hypoxia in glioma cells

Glunde, Kristine; Düßmann, Heiko; Juretschke, Hans-Paul; Leibfritz, Dieter

doi:10.1046/j.0022-3042.2001.00661.x

Cited by 33 publications

(27 citation statements)

References 42 publications

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“…This increased pH i recovery rate was due to stimulated NHE1 activity because the increased rate was absent in astrocytes treated with HOE642 or astrocytes from NHE1 null mice. HOE642 also protected the energy state (i.e., [phosphocreatine]/[creatine] ratio) of glioma cells during two hours of hypoxia (Glunde et al, 2002). This last observation is consistent with the hypothesis that NHE activity rises even during the hypoxic stress.…”

Section: Introductionsupporting

confidence: 87%

Effects of acute hypoxia on intracellular-pH regulation in astrocytes cultured from rat hippocampus

Bevensee

Boron

2008

Brain Research

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We used the pH-sensitive dye BCECF to evaluate the effect of acute (5-10 min) hypoxia (∼3% O 2 ) on the regulation of intracellular pH (pH i ) in astrocyte populations cultured from rat hippocampus. For cells in the nominal absence of CO 2 / at an extracellular pH of 7.40 (37°C), acute hypoxia caused a small (0.05) decrease in steady-state pH i , but increased the pH i -recovery rate from an acid load during all but the late phase of the pH i recovery. During such pH i recoveries, the total acidextrusion rate (φ E , the product of dpH i /dt and proton buffering power) decreased with increasing pH i . Hypoxia alkali shifted the plot of φ E vs. pH i ; over the upper ∼85% of the φ E range, this shift was 0.15-0.30. Hypoxia also stimulated the pH i -recovery rate from an alkali load. Under normoxic conditions, switching the extracellular buffer to 5% CO 2 /22 mM also alkali shifted the φ EpH i plot (upper ∼85%) by 0.4-0.5. Superimposing hypoxia on CO 2 / further alkali shifted the φ E -pH i plot (upper ∼85% of the φ E range) by 0.05-0.15. The SITS-insensitive component of φ E was alkali shifted by 0.20-0.30, whereas the SITS-sensitive component of φ E was depressed in the low pH i range. Thus, in the nominal absence of CO 2 / , acute hypoxia has little effect on steady-state pH i but stimulates acid extrusion and acid loading, whereas in the presence of CO 2 / , hypoxia stimulates the SITS-insensitive but inhibits the SITS-sensitive acid extrusion.

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Section: Introductionsupporting

confidence: 87%

Effects of acute hypoxia on intracellular-pH regulation in astrocytes cultured from rat hippocampus

Bevensee

Boron

2008

Brain Research

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“…In this context, it is relevant to mention that such a suppression of NHE-1 has been shown by extracellular aci- dosis in other cell types (35). Although in our population we did not measure intracellular pH, this suppression may contribute to a reported cellular acidosis similar to what has already been reported in IBD (9,10).…”

Section: Discussionmentioning

confidence: 59%

Role of Na⁺/H⁺Exchanger Isoform-1 in Human Inflammatory Bowel Disease

Khan

Siddique

Al-Awadi

et al. 2003

Canadian Journal of Gastroenterology

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BACKGROUND: Na + /H + exchanger (NHE) is responsible for a net uptake of sodium chloride and water from the gastrointestinal tract and maintains electrolyte and water homeostasis. However, its status in human inflammatory bowel disease such as ulcerative colitis (UC) and Crohn's disease (CD) remains poorly understood. OBJECTIVES: To investigate the role of NHE-1 isoform in human CD and UC. METHODS: Expression of NHE-1 protein and messenger ribonucleic acid and sodium pump activity were examined in the colonic biopsy samples taken from UC (n=11) and CD (n=13) patients using enhanced chemiluminescence-Western blot analysis, reverse transcription polymerase chain reaction and spectrophotometry. Subjects presenting with abdominal pain and endoscopically normal colon served as normal controls (n=11). Myeloperoxidase (MPO) activity and histology were performed to confirm tissue inflammation. RESULTS: MPO activity increased significantly (P<0.05) in both UC and CD patients compared with the normal controls. Parallel to MPO activity profile, there was also a significantly higher infiltration of inflammatory cells in both cases. P-nitrophenylphosphatase activity, a marker of the sodium pump, remained unchanged in CD but increased significantly (P<0.05) in UC compared with the normal controls. On the contrary, the level of NHE-1 protein and messenger ribonucleic acid was significantly decreased (P<0.05) in both cases, whereas the internal control, a-actin remained unaltered. CONCLUSIONS: These findings demonstrate a transcriptionally regulated suppression of NHE-1 in both UC and CD. This NHE-1 suppression may reduce an uptake of sodium chloride and water from the inflamed colonic lumen and thus contribute to diarrhea and neuromuscular alterations in these conditions.

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“…NHE-1 is the most important pHi regulator; its expression and activity impacts the stability of cellular pHi, which is the most basic condition required for cell growth (39). When altered, pHi can impact cell growth and function directly, so expression and activity of NHE-1 plays an important role in cell growth (40). An inhibitor of NHE-1 could inhibit cell growth by affecting these processes.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of proliferation and apoptosis induced by a Na+/H+ exchanger-1 (NHE-1) antisense gene on drug-resistant human small cell lung cancer cells

Bao²,

Li³

et al. 2009

Oncol Rep

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Abstract. The goal of this study was to evaluate the effect of the Na + /H + exchanger-1 (NHE-1) antisense gene on drugresistant human small cell lung cancer (SCLC) cell proliferation and apoptosis. A recombinant NHE-1 antisense gene was transfected into drug-resistant human SCLC H446/CDDP cells. Intracellular pH (pHi) was measured with fluorescence spectrophotometry. Cell proliferation was assayed cytometrically, and expression of the apoptosis gene caspase-3 was assayed using immunohistochemistry. Apoptosis and the cell cycles were imaged using a flow cytometer. pHi decreased significantly in transfected cells compared with control cells transfected with an empty vector (6.86±0.01 and 7.25±0.02, respectively, P<0.01). Cell proliferation began to decrease 48 h after antisense gene transfection, and the expression of the caspase-3 was stronger in transfected cells compared to the control group. The drug resistant exponent was significantly decreased (P<0.01), and there were more cells in G1 in the transfected group compared to the control group (70 and 57%, respectively, P<0.05). The rate of apoptosis in transfected cells was significantly higher than in the control group (12.18±1.86 and 2.37±0.33%, respectively, P<0.01). The NHE-1 antisense gene was able to induce drugresistant human SCLC H446/CDDP cells to become acidified and apoptotic, which could provide a novel therapy for multidrug resistance SCLC. IntroductionSmall cell lung cancer (SCLC) is a non-resectable and highly metastatic neoplastic disease, accounting for about 20% of all lung cancers (1). It is particularly aggressive and has a poor prognosis, with the 5-year survival rate at diagnosis rarely exceeding 10% (2). SCLC is a chemosensitive and radiosensitive disease; chemotherapy for SCLC typically involves a combination of etoposide, doxorubicin, vincristine, paclitaxel, and platinum-based regimens (3-5). First-line combination chemotherapy (with or without regional radiotherapy) induces a positive response in 70% of patients, with 50% of patients showing complete remission (6,7). However, 90% of these complete remission patients relapse with multidrug resistant tumours, making chemotherapy ineffective (8,9). Multidrug resistance is a serious clinical problem, which often severely limits the effectiveness of cancer chemotherapy (10). Thus, treating SCLC presents a significant clinical challenge.However, an effective way to treat SCLC multi-drug resistance has been reported (11). NHE-1 can directly interact with other regulatory cellular signaling pathways and is a multifaceted regulator of cell migration, proliferation, and cell death (12-14). The Na + /H + exchanger NHE-1 isoform is expressed ubiquitously and plays the crucial role of regulating intracellular pH by catalyzing the exchange of one extracellular sodium ion against one intracellular proton. Maintaining a steady-state intracellular pH during physiological conditions requires the continuous cellular export of acidic equivalents (15,16). Na + /H + exchangers (NHE) are membrane transport...

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Na⁺/H⁺ exchange subtype 1 inhibition during extracellular acidification and hypoxia in glioma cells

Cited by 33 publications

References 42 publications

Effects of acute hypoxia on intracellular-pH regulation in astrocytes cultured from rat hippocampus

Effects of acute hypoxia on intracellular-pH regulation in astrocytes cultured from rat hippocampus

Role of Na⁺/H⁺Exchanger Isoform-1 in Human Inflammatory Bowel Disease

Inhibition of proliferation and apoptosis induced by a Na+/H+ exchanger-1 (NHE-1) antisense gene on drug-resistant human small cell lung cancer cells

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Na+/H+ exchange subtype 1 inhibition during extracellular acidification and hypoxia in glioma cells

Cited by 33 publications

References 42 publications

Effects of acute hypoxia on intracellular-pH regulation in astrocytes cultured from rat hippocampus

Effects of acute hypoxia on intracellular-pH regulation in astrocytes cultured from rat hippocampus

Role of Na+/H+Exchanger Isoform-1 in Human Inflammatory Bowel Disease

Inhibition of proliferation and apoptosis induced by a Na+/H+ exchanger-1 (NHE-1) antisense gene on drug-resistant human small cell lung cancer cells

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Na⁺/H⁺ exchange subtype 1 inhibition during extracellular acidification and hypoxia in glioma cells

Role of Na⁺/H⁺Exchanger Isoform-1 in Human Inflammatory Bowel Disease