Na+:H+ exchange inhibition induces intracellular acidosis and differentially impairs cell growth and viability of human and rat hepatocarcinoma cells

García-Cañero, R.; Trilla, Carolina; Diego, Javier Pérez de; Díaz-Gil, Juan José; Cobo, José M.

doi:10.1016/s0378-4274(99)00072-7

Cited by 21 publications

(12 citation statements)

References 34 publications

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“…However, a number of studies have suggested that activity of the Na ϩ /H ϩ exchanger is critical for growth and viability of the human liver and related cell types. Recently, it has been shown that Na ϩ /H ϩ exchanger inhibition impairs cell growth and viability of human and rat hepatocarcinoma cells (19). Also, in hepatic stellate cells, Na ϩ /H ϩ exchange inhibition prevents cell proliferation (10), and Na ϩ /H ϩ exchanger activation may play a critical role in growth of some hepatic tumors (43).…”

Section: Discussionmentioning

confidence: 99%

Developmental regulation of Na⁺/H⁺exchanger expression in fetal and neonatal mice

Rieder

Fliegel

2002

American Journal of Physiology-Heart and Circulatory Physiology

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We examined the hypothesis that Na+/H+ exchanger expression is regulated during fetal and neonatal development and differentiation. To examine transcriptional regulation of the NHE1 isoform of the Na+/H+ exchanger, transgenic mice were created that contained the mouse NHE1 promoter driving expression of green fluorescent protein. The level of NHE1 transcription varied between tissues and with the stage of embryonic development. The highest expression was in the heart and liver of 12- to 15-day-old mice, and this declined with age. To examine Na+/H+exchanger protein levels, we immunoblotted mouse tissues from 18-day-old embryos, neonates, and adults. Protein levels increased after embryonic day 18 and peaked at 14 days of age in the heart, lung, liver, kidney, and brain. The greatest rise in NHE1 protein expression occurred in the heart, whereas the smallest increase was in the brain. The results suggest that Na+/H+ exchanger transcription and protein levels are controlled in a tissue-specific and time-dependent manner during development.

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Section: Discussionmentioning

confidence: 99%

Developmental regulation of Na⁺/H⁺exchanger expression in fetal and neonatal mice

Rieder

Fliegel

2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…Recent investigations have shown that the treatment of cells with ouabain and amiloride not only inhibits the monovalent ion¯uxes through the plasma membrane, but also induces various cellular signaling pathways [20,21], e.g. via protein kinases and transcription factors NFkappaB and AP-1 [20].…”

Section: Discussionmentioning

confidence: 99%

Cell attachment to extracellular matrices is modulated by pulsed radiation at 820 nm and chemicals that modify the activity of enzymes in the plasma membrane

Karu

Pyatibrat

Kalendo³

2001

Lasers Surg Med

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The results obtained indicate that pulsed IR radiation at 820 nm increases the cell-matrix attachment. It is the modulation of the monovalent ion fluxes through the plasma membrane and not the release of arachidonic acid that is involved in the cellular signaling pathways activated by irradiation at 820 nm. Preirradiation has a protective effect against the inhibitive action of ouabain, arachidonic acid, ATP, and quinacrine on cell attachment process. It is supposed that irradiation activates those signaling pathways in cells which attenuate the inhibitive action of these chemicals.

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“…Amiloride is a less selective inhibitor of sodium-hydrogen exchange than cariporide and has been reported to have antiproliferative effects on several cancer cell lines (Horvat et al, 1992;Hasuda et al, 1994;García-Cañ ero et al, 1999), including U118 glioma cells (SzolgayDaniel et al, 1991). Amiloride at 50 or 500 M maximally reduced pH i in U87 glioma cells loaded with BCECF from 7.37 to 7.05 within 50 min (Table 1).…”

Section: Effects Of Reduced Intracellular Ph On Glioma Cellmentioning

confidence: 99%

Amiloride Kills Malignant Glioma Cells Independent of Its Inhibition of the Sodium-Hydrogen Exchanger

Hegde¹,

Roscoe²,

Cala

et al. 2004

J Pharmacol Exp Ther

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Previously, we demonstrated that malignant glioma cell lines have increased intracellular pH (pH i ) as a result of increased activities of the type I sodium/hydrogen exchanger (NHE1). This alkalotic pH i of 7.2 to 7.4 is favorable for augmented glycolysis, DNA synthesis, and cell cycle progression. Conversely, reductions in pH i have been associated with reduced rates of proliferation in transformed cell types. The effects of reducing pH i directly and by NHE1 inhibition on human malignant glioma cells were systematically compared with those on primary rat astrocytes. Neither cariporide, nor direct acidification to pH i 6.9 altered the proliferative rates or viabilities of human U87 or U118 malignant glioma cell lines. However, amiloride significantly impaired glioma cell proliferation and viability while not affecting astrocytes at concentrations (500 M) that exceeded its inhibition of NHE1 in glioma cells (IC 50 ϭ 17 M). Preventing a reduction of pH i did not alter the drug's antiproliferative and cytotoxic effects on glioma cells. These findings indicated that amiloride's cytotoxic effects on glioma cells are independent of its ability to inhibit NHE1 or to reduce intracellular pH i . The amiloride derivative 2,4 dichlorobenzamil (DCB) inhibits the sodium-calcium exchanger (NCX) and was both antiproliferative and cytotoxic to glioma cells at low doses (20 M).preferentially blocks sodiumdependent calcium influx by NCX (reverse mode) and was nontoxic to glioma cells. It is proposed that DCB (20 M) and amiloride (500 M) impair calcium efflux by NCX, leading to elevations of intracellular calcium that initiate a morphologically necrotic, predominantly caspase-independent glioma cell death.High-grade malignant gliomas are the most common, lethal primary brain tumor in adults (Legler, 1999). Median survival is approximately 9 to 12 months after diagnosis (Stewart, 2002), and the tumors are usually refractory to aggressive multimodal therapy (Brandes et al., 1999). Glioma cells exhibit increased glycolytic fluxes associated with elevated lactate/pyruvate ratios (Miccoli et al., 1996) and would be expected to have an acidotic intracellular pH (pH i ). However, several 31 P spectroscopic studies measured intracellular human glioma pH in situ and reported alkaline values (pH 7.12-7.24) compared with surrounding brain (pH 6.99 -7.05) (Hubesch et al., 1990;Rutter et al., 1995). The alkaline pH is more optimal for obligate tumor glycolysis, DNA synthesis, and cell cycle progression (Hasuda et al., 1994;Miccoli et al., 1996;Katabi et al., 1999). In addition, a reduction in pH i has been associated with reduced rates of proliferation and growth arrest in transformed cell types (Musgrove et al., 1987;Rotin et al., 1989;Horvat et al., 1992).Our earlier investigation of four human and rat malignant glioma cell lines revealed an alkaline intracellular pH (pH i of 7.31-7.48) compared with primary rat astrocytes (pH i of 6.98 Ϯ 0.01) (McLean et al., 2000). Increased activity of the type 1 Na ϩ -H ϩ exchanger (NHE1) in gl...

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Na+:H+ exchange inhibition induces intracellular acidosis and differentially impairs cell growth and viability of human and rat hepatocarcinoma cells

Cited by 21 publications

References 34 publications

Developmental regulation of Na⁺/H⁺exchanger expression in fetal and neonatal mice

Developmental regulation of Na⁺/H⁺exchanger expression in fetal and neonatal mice

Cell attachment to extracellular matrices is modulated by pulsed radiation at 820 nm and chemicals that modify the activity of enzymes in the plasma membrane

Amiloride Kills Malignant Glioma Cells Independent of Its Inhibition of the Sodium-Hydrogen Exchanger

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Na+:H+ exchange inhibition induces intracellular acidosis and differentially impairs cell growth and viability of human and rat hepatocarcinoma cells

Cited by 21 publications

References 34 publications

Developmental regulation of Na+/H+exchanger expression in fetal and neonatal mice

Developmental regulation of Na+/H+exchanger expression in fetal and neonatal mice

Cell attachment to extracellular matrices is modulated by pulsed radiation at 820 nm and chemicals that modify the activity of enzymes in the plasma membrane

Amiloride Kills Malignant Glioma Cells Independent of Its Inhibition of the Sodium-Hydrogen Exchanger

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Developmental regulation of Na⁺/H⁺exchanger expression in fetal and neonatal mice

Developmental regulation of Na⁺/H⁺exchanger expression in fetal and neonatal mice