4-aminopyridine causes apoptosis and blocks an outward rectifier K+ channel in malignant astrocytoma cell lines

Ls, Chin; Park, CC; Km, Zitnay; Sinha, Mala; Aj, DiPatri; Perillan, P. R.; Jm, Simard

doi:10.1002/(sici)1097-4547(19970415)48:2<122::aid-jnr4>3.0.co;2-e

Cited by 96 publications

(36 citation statements)

References 23 publications

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“…Inhibiting K ϩ channels by TEA or 4-AP are protective against apoptosis in several cell types (Yu et al, 1997;Colom et al, 1998;Dallaporta et al, 1999;Wang et al, 1999Wang et al, , 2000Krick et al, 2001); on the other hand, 4-AP is toxic in malignant astrocytoma cell lines and HepG2 human hepatoblastoma cells (Chin et al, 1997;Kim et al, 2000). Our data suggest that blocking the Na ϩ ,K ϩ -ATPase, but not the K ϩ channels, is likely the primary mechanism underlying the Apoptotic and necrotic morphological alterations were examined by electron microscopy.…”

Section: Discussionmentioning

confidence: 99%

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Block of Na⁺,K⁺-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons

Wang¹,

Xiao²,

Yang³

et al. 2003

J Pharmacol Exp Ther

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Kϩ channel blockers such as 4-aminopyridine (4-AP) can be toxic to neurons; the cellular mechanism underlying the toxicity, however, is obscure. In cultured mouse cortical neurons, we tested the hypothesis that the toxic effect of 4-AP might result from inhibiting the Na ϩ ,K ϩ -ATPase (Na ϩ ,K ϩ -pump) and thereafter induction of a hybrid death of concomitant apoptosis and necrosis. The Na ϩ ,K ϩ -pump activity, monitored as whole-cell membrane currents, was markedly blocked by 4-AP in concentration-and voltage-dependent manners in low millimolar ranges. At similar concentrations, 4-AP induced a neuronal death sensitive to attenuation by the caspase inhibitor Z-VAD-FMK (Z-Val-Ala-Asp(OMe)-fluoromethyl ketone) or Ca 2ϩ chelator BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid-acetoxymethyl ester). Electron microscopy confirmed hybrid ultrastructural features of coexisting apoptotic and necrotic components in same cells. We suggest that 4-AP is a potent antagonist of the Na ϩ ,K ϩ -ATPase and an inducer of the hybrid death of central neurons.Aminopyridines, particularly 4-aminopyridine (4-AP), have been investigated as a means of beneficial symptomatic treatment in a variety of neurological conditions of demyelination diseases including multiple sclerosis, myasthenia gravis, and spinal cord injury (Murray and Newsom-Davis, 1981; Jones et al

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Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that 4-AP, at commonly used concentrations, can cause apoptosis in hepatoblastoma cells (Kim et al, 2000) and malignant astrocytoma cell lines (Chin et al, 1997). Another classical K ϩ channel blocker tetraethylammonium (TEA) at high concentrations also shows toxic effects on cortical neurons (Yu et al, 1997).…”

mentioning

confidence: 99%

Block of Na⁺,K⁺-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons

Wang¹,

Xiao²,

Yang³

et al. 2003

J Pharmacol Exp Ther

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“…Along those lines, the pharmacological inhibition of K þ channels may compromise cell proliferation [100,101]. The cell membrane of tumour cells is, however, rather depolarized compared with excitable cells, epithelia or differentiated glial cells [102].…”

Section: K þ Channelsmentioning

confidence: 99%

Ion channels in cancer: future perspectives and clinical potential

Läng

Stournaras

2014

Phil. Trans. R. Soc. B

138

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Ion transport across the cell membrane mediated by channels and carriers participate in the regulation of tumour cell survival, death and motility. Moreover, the altered regulation of channels and carriers is part of neoplastic transformation. Experimental modification of channel and transporter activity impacts tumour cell survival, proliferation, malignant progression, invasive behaviour or therapy resistance of tumour cells. A wide variety of distinct Ca 2+ permeable channels, K + channels, Na + channels and anion channels have been implicated in tumour growth and metastasis. Further experimental information is, however, needed to define the specific role of individual channel isoforms critically important for malignancy. Compelling experimental evidence supports the assumption that the pharmacological inhibition of ion channels or their regulators may be attractive targets to counteract tumour growth, prevent metastasis and overcome therapy resistance of tumour cells. This short review discusses the role of Ca 2+ permeable channels, K + channels, Na + channels and anion channels in tumour growth and metastasis and the therapeutic potential of respective inhibitors.

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“…Cellular K ϩ loss has previously been shown to be one determinant of eryptosis (48). Similarly, cellular K ϩ loss has been implicated in the apoptosis of nucleated cells under a variety of conditions (12,20,54,61,76,79), including stimulation of TNF receptors (32), CD95 activation (34,71), glucocorticoid (7,80,81), GABA (30) or dopamine (60) treatment, growth factor depletion (72), thyroid status (3), sulfonylureas (5), etoposide treatment (69), transformation (77), choline deficiency (2), glutamine depletion (68), oxidative stress (8,62), hypoxia (53), radiation (67), sphingosine treatment (21), amyloid treatment (18), staurosporine (63), urea (56), Cl Ϫ channel blockers (73), and K ϩ channel blockers (17). However, the evidence for a causal role of K ϩ channels in the enhanced susceptibility of tg6 erythrocytes to eryptosis is at present circumstantial.…”

Section: CLmentioning

confidence: 99%

Enhanced susceptibility to suicidal death of erythrocytes from transgenic mice overexpressing erythropoietin

Föller¹,

Kasinathan²,

Koka³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Eryptosis, a suicidal death of mature erythrocytes, is characterized by decrease of cell volume, cell membrane blebbing, and breakdown of cell membrane asymmetry with phosphatidylserine exposure at the cell surface. Triggers of eryptosis include increased cytosolic Ca2+ activity, which could result from activation of Ca2+-permeable cation channels. Ca2+ triggers phosphatidylserine exposure and activates Ca2+-sensitive K+ channels, leading to cellular K+ loss and cell shrinkage. The cation channels and thus eryptosis are stimulated by Cl− removal and inhibited by erythropoietin. The present experiments explored eryptosis in transgenic mice overexpressing erythropoietin (tg6). Erythrocytes were drawn from tg6 mice and their wild-type littermates (WT). Phosphatidylserine exposure was estimated from annexin binding and cell volume from forward scatter in fluorescence-activated cell sorting (FACS) analysis. The percentage of annexin binding was significantly larger and forward scatter significantly smaller in tg6 than in WT erythrocytes. Transgenic erythrocytes were significantly more resistant to osmotic lysis than WT erythrocytes. Cl− removal and exposure to the Ca2+ ionophore ionomycin (1 μM) increased annexin binding and decreased forward scatter, effects larger in tg6 than in WT erythrocytes. The K+ ionophore valinomycin (10 nM) triggered eryptosis in both tg6 and WT erythrocytes and abrogated differences between genotypes. An increase of extracellular K+ concentration to 125 mM blunted the difference between tg6 and WT erythrocytes. Fluo-3 fluorescence reflecting cytosolic Ca2+ activity was larger in tg6 than in WT erythrocytes. In conclusion, circulating erythrocytes from tg6 mice are sensitized to triggers of eryptosis but more resistant to osmotic lysis, properties at least partially due to enhanced Ca2+ entry and increased K+ channel activity.

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4-aminopyridine causes apoptosis and blocks an outward rectifier K+ channel in malignant astrocytoma cell lines

Cited by 96 publications

References 23 publications

Block of Na⁺,K⁺-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons

Block of Na⁺,K⁺-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons

Ion channels in cancer: future perspectives and clinical potential

Enhanced susceptibility to suicidal death of erythrocytes from transgenic mice overexpressing erythropoietin

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4-aminopyridine causes apoptosis and blocks an outward rectifier K+ channel in malignant astrocytoma cell lines

Cited by 96 publications

References 23 publications

Block of Na+,K+-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons

Block of Na+,K+-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons

Ion channels in cancer: future perspectives and clinical potential

Enhanced susceptibility to suicidal death of erythrocytes from transgenic mice overexpressing erythropoietin

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Product

Resources

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Block of Na⁺,K⁺-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons

Block of Na⁺,K⁺-ATPase and Induction of Hybrid Death by 4-Aminopyridine in Cultured Cortical Neurons