In vitro and in vivo pharmacology of a structurally novel Na+‐H+ exchange inhibitor, T‐162559

Kusumoto, Keiji; Igata, Hideki; Abe, Akemi; Ikeda, Shota; Tsuboi, Ayako; Imamiya, Eiko; Fukumoto, Shoji; Shiraishi, Masayuki; Watanabe, Toshifumi

doi:10.1038/sj.bjp.0704647

Cited by 23 publications

(7 citation statements)

References 41 publications

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“…Amiloride and its derivatives are weak bases, with reported pK a values ranging between 8.5 and 8.7 for amiloride, DMA, HMA, and EIPA 15,34 . In contrast, cariporide and eniporide are weak acids, with pK a values of around 6.2 and 6.0, respectively 35,36 . We therefore speculated that the cytotoxicity of pyrazinoylguanidine-type NHE1 inhibitors might reflect their accumulation in acidic organelles during spheroid growth.…”

Section: Cytotoxic Effects Of Other Nhe1 Inhibitors In Mcf-7 and Mda-mentioning

confidence: 96%

“…reduced drug concentration at the site of action 12,23 . The benzoylguanidine-type inhibitors cariporide and eniporide are weak acids with pK a values of 6.2 and 6.0, respectively 35,36 . Based on their chemical properties, they are thus expected to preferentially partition into the cytosol, whereas the pyrazinoylguanidines, which are weak bases (pK a values 8.5-8.7 15,34 ), should partition into acidic compartments.…”

Section: Pyrazinoylguanidine Cytotoxicity In 3d Is Associated With Inmentioning

confidence: 99%

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Pyrazine ring-based Na+/H+ exchanger (NHE) inhibitors potently inhibit cancer cell growth in 3D culture, independent of NHE1

Rolver¹,

Elingaard-Larsen²,

Andersen³

et al. 2020

Sci Rep

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the na + /H + exchanger-1 (NHE1) supports tumour growth, making NHE1 inhibitors of interest in anticancer therapy, yet their molecular effects are incompletely characterized. Here, we demonstrate that widely used pyrazinoylguanidine-type NHE1 inhibitors potently inhibit growth and survival of cancer cell spheroids, in a manner unrelated to NHE1 inhibition. Cancer and non-cancer cells were grown as 3-dimensional (3D) spheroids and treated with pyrazinoylguanidine-type (amiloride, 5-(N-ethyl-Nisopropyl)-amiloride (EIPA), 5-(N,N-dimethyl)-amiloride (DMA), and 5-(N,N-hexamethylene)-amiloride (HMA)) or benzoylguanidine-type (eniporide, cariporide) NHE1 inhibitors for 2-7 days, followed by analyses of viability, compound accumulation, and stress-and death-associated signalling. EIPA, DMA and HMA dose-dependently reduced breast cancer spheroid viability while cariporide and eniporide had no effect. Although both compound types inhibited NHE1, the toxic effects were NHE1-independent, as inhibitor-induced viability loss was unaffected by NHE1 CRISPR/Cas9 knockout. EIPA and HMA accumulated extensively in spheroids, and this was associated with marked vacuolization, apparent autophagic arrest, ER stress, mitochondrial-and DNA damage and poly-ADP-ribose-polymerase (PARP) cleavage, indicative of severe stress and paraptosis-like cell death. Pyrazinoylguanidine-induced cell death was partially additive to that induced by conventional anticancer therapies and strongly additive to extracellular-signal-regulated-kinase (ERK) pathway inhibition. Thus, in addition to inhibiting NHE1, pyrazinoylguanidines exert potent, NHE1-independent cancer cell death, pointing to a novel relevance for these compounds in anticancer therapy.

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Section: Cytotoxic Effects Of Other Nhe1 Inhibitors In Mcf-7 and Mda-mentioning

confidence: 96%

Section: Pyrazinoylguanidine Cytotoxicity In 3d Is Associated With Inmentioning

confidence: 99%

Pyrazine ring-based Na+/H+ exchanger (NHE) inhibitors potently inhibit cancer cell growth in 3D culture, independent of NHE1

Rolver¹,

Elingaard-Larsen²,

Andersen³

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…1), to determine if NHE-1 activity is involved in platelet aggregation. Prior work has demonstrated that the specific and selective NHE-1 inhibitors cariporide [12, 15], eniporide [14, 15], zoniporide [13], T-162559 [15] and KR-32570 [16] inhibit platelet NHE-1 activity. Furthermore, the structural analogue BIIB722, which contain a 3-methylfluoronyl group in place of the 3-methylsulfonyl group in BIIB 513, also has been shown to inhibit platelet NHE-1 activity as measured by the platelet swelling assay [27].…”

Section: Discussionmentioning

confidence: 99%

Effect on ex vivo platelet aggregation and in vivo cyclic flow with Na+/H+ exchange inhibition

Gumina

Newman

Gross

2010

J Thromb Thrombolysis

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BIIB 513 and EMD 85131 are selective inhibitors of the Na+/H+ exchanger-1 (NHE-1) that are benzoylguanidine derivatives of the clinically employed diuretic amiloride. Prior studies have suggested a role for NHE-1 activity in platelet activation and aggregation using amiloride or its non-benzoylguanidines derivatives. However, the concentrations employed in these prior studies were at levels known to exert effects on other ion transport systems besides the NHE-1. Therefore, the purpose of this study was to examine the effects of more selective NHE-1 inhibitors, BIIB 513 and EMD 85131, on platelet aggregation and in vivo cyclic flow following arterial injury. BIIB 513 and EMD 85131 effects on ex vivo canine and human platelet aggregation in response to various agents was monitored via platelet aggregation. For analysis of in vivo thrombus formation, a femoral artery crush injury model was employed and a flow meter was used to monitor the effect of BIIB 513 on cyclic blood flow. Treatment of either canine or human platelets with up to 1 mM of BIIB 513 had no effect on aggregation induced by platelet activating factor (PAF), thrombin receptor activator peptide (TRAP), or adenosine diphosphate (ADP). Additionally, the structurally related compound EMD 85131 at up to 1 mM failed to inhibit TRAP induced platelet aggregation. In vivo administration of up to 9 mg/kg of BIIB 513 intravenously failed to affect cyclic flow in a canine model of femoral artery injury. These data demonstrate that the specific and selective NHE-1 inhibitors BIIB 513 or EMD 85131 have no effect on ex vivo platelet aggregation or in vivo cyclic flow following arterial injury.

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“…T-162559 ( Fig. 1), an aminoguanidine derivative with a more potent NHE1 inhibitory effect against ischemia and reperfusion injury than cariporide and eniporide [15,16], encouraged us to identify a novel NHE1 inhibitor with an aminoguanidine group. Previously, we found that the inhibitory effect of 2-benzimidazol-2-ylthio-1-(4-nitro phenylethylidene) aminoguanidine (CPU-X-050519, IC 50 ¼ 1.17 nM) (Fig.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and bioactivity of substituted indan-1-ylideneaminoguanidine derivatives

Zhang

Dong

et al. 2009

European Journal of Medicinal Chemistry

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In vitro and in vivo pharmacology of a structurally novel Na⁺‐H⁺ exchange inhibitor, T‐162559

Cited by 23 publications

References 41 publications

Pyrazine ring-based Na+/H+ exchanger (NHE) inhibitors potently inhibit cancer cell growth in 3D culture, independent of NHE1

Pyrazine ring-based Na+/H+ exchanger (NHE) inhibitors potently inhibit cancer cell growth in 3D culture, independent of NHE1

Effect on ex vivo platelet aggregation and in vivo cyclic flow with Na+/H+ exchange inhibition

Synthesis and bioactivity of substituted indan-1-ylideneaminoguanidine derivatives

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