Na+/H+-exchange inhibition by cariporide is compensated via Na+,HCO3−-cotransport and has no net growth consequences for ErbB2-driven breast carcinomas

Article

Author: Antony, Arththy ; Cornett, Claus ; Kristensen, Kristoffer B ; Hansen, Steen H ; Boedtkjer, Ebbe ; Pedersen, Stine F ; Aaen, Pernille

Defense against intracellular acidification of breast cancer tissue depends on net acid extrusion via Na⁺,HCO₃^--cotransporter NBCn1/Slc4a7 and Na⁺/H⁺-exchanger NHE1/Slc9a1. NBCn1 is increasingly recognized as breast cancer susceptibility protein and promising therapeutic target, whereas evidence for targeting NHE1 is discordant. Currently, selective small molecule inhibitors exist against NHE1 but not NBCn1. Cellular assays-with some discrepancies-link NHE1 activity to proliferation, migration, and invasion; and disrupted NHE1 expression can reduce triple-negative breast cancer growth. Studies on human breast cancer tissue associate high NHE1 expression with reduced metastasis and-in some molecular subtypes-improved patient survival. Here, we evaluate Na⁺/H⁺-exchange and therapeutic potential of the NHE1 inhibitor cariporide/HOE-642 in murine ErbB2-driven breast cancer. Ex vivo, cariporide inhibits net acid extrusion in breast cancer tissue (IC₅₀ = 0.18 μM) and causes small decreases in steady-state intracellular pH (pH_i). In vivo, we deliver cariporide orally, by osmotic minipumps, and by intra- and peritumoral injections to address the low oral bioavailability and fast metabolism. Prolonged cariporide administration in vivo upregulates NBCn1 expression, shifts pH_i regulation towards CO₂/HCO₃^--dependent mechanisms, and shows no net effect on the growth rate of ErbB2-driven primary breast carcinomas. Cariporide also does not influence proliferation markers in breast cancer tissue. Oral, but not parenteral, cariporide elevates serum glucose by ∼1.5 mM. In conclusion, acute administration of cariporide ex vivo powerfully inhibits net acid extrusion from breast cancer tissue but lowers steady-state pH_i minimally. Prolonged cariporide administration in vivo is compensated via NBCn1 and we observe no discernible effect on growth of ErbB2-driven breast carcinomas.

31 Jul 2024·Cardiovascular Research

Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF

Article

Author: Hegner, Philipp ; Schmid, Christof ; Hamdani, Nazha ; Keller, Karoline ; Klatt, Susanne ; Lebek, Simon ; Maier, Lars ; Reuthner, Kathrin ; Arzt, Michael ; Riechel, Johannes ; Provaznik, Zdenek ; Wester, Michael ; Heers, Silvia ; Schollmeier, Elisa ; Trum, Maximilian ; Wagner, Stefan

AbstractAimsHeart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodelling and atrial fibrillation are frequently observed in HFpEF. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have recently been shown to improve clinical outcomes in HFpEF, and post-hoc analyses suggest atrial anti-arrhythmic effects. We tested if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx, which is known to cause atrial arrhythmias, and if that is responsive to treatment with the SGTL2i empagliflozin.Methods and resultsCardiomyocytes were isolated from atrial biopsies of 124 patients (82 with HFpEF) undergoing elective cardiac surgery. Na influx was measured with the Na-dye Asante Natrium Green–2 AM (ANG-2). Compared to patients without heart failure (NF), Na influx was doubled in HFpEF patients (NF vs. HFpEF: 0.21 ± 0.02 vs. 0.38 ± 0.04 mmol/L/min (N = 7 vs. 18); P = 0.0078). Moreover, late INa (measured via whole-cell patch clamp) was significantly increased in HFpEF compared to NF. Western blot and HDAC4 pulldown assay indicated a significant increase in CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation in HFpEF compared to NF, whereas NaV1.5 protein and mRNA abundance remained unchanged. Consistently, increased Na influx was significantly reduced by treatment not only with the CaMKII inhibitor autocamtide-2-related inhibitory peptide (AIP), late INa inhibitor tetrodotoxin (TTX) but also with sodium/hydrogen exchanger 1 (NHE1) inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late INa in HFpEF. Multivariate linear regression analysis, adjusting for important clinical confounders, revealed HFpEF to be an independent predictor for changes in Na handling in atrial cardiomyocytes.ConclusionWe show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late INa and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late INa, which could contribute to anti-arrhythmic effects in patients with HFpEF.

01 May 2024·Biomedicine & Pharmacotherapy

Empagliflozin mitigates cardiac hypertrophy through cardiac RSK/NHE-1 inhibition

Article

Author: Weber, Nina C ; Ghouse, Zakiya ; Coronel, Ruben ; Hollmann, Markus W ; Chen, Sha ; Zuurbier, Coert J ; Overberg, Kenneth

BACKGROUNDSGLT2i reduce cardiac hypertrophy, but underlying mechanisms remain unknown. Here we explore a role for serine/threonine kinases (STK) and sodium hydrogen exchanger 1(NHE1) activities in SGLT2i effects on cardiac hypertrophy.METHODSIsolated hearts from db/db mice were perfused with 1 µM EMPA, and STK phosphorylation sites were examined using unbiased multiplex analysis to detect the most affected STKs by EMPA. Subsequently, hypertrophy was induced in H9c2 cells with 50 µM phenylephrine (PE), and the role of the most affected STK (p90 ribosomal S6 kinase (RSK)) and NHE1 activity in hypertrophy and the protection by EMPA was evaluated.RESULTSIn db/db mice hearts, EMPA most markedly reduced STK phosphorylation sites regulated by RSKL1, a member of the RSK family, and by Aurora A and B kinases. GO and KEGG analysis suggested that EMPA inhibits hypertrophy, cell cycle, cell senescence and FOXO pathways, illustrating inhibition of growth pathways. EMPA prevented PE-induced hypertrophy as evaluated by BNP and cell surface area in H9c2 cells. EMPA blocked PE-induced activation of NHE1. The specific NHE1 inhibitor Cariporide also prevented PE-induced hypertrophy without added effect of EMPA. EMPA blocked PE-induced RSK phosphorylation. The RSK inhibitor BIX02565 also suppressed PE-induced hypertrophy without added effect of EMPA. Cariporide mimicked EMPA's effects on PE-treated RSK phosphorylation. BIX02565 decreased PE-induced NHE1 activity, with no further decrease by EMPA.CONCLUSIONSRSK inhibition by EMPA appears as a novel direct cardiac target of SGLT2i. Direct cardiac effects of EMPA exert their anti-hypertrophic effect through NHE-inhibition and subsequent RSK pathway inhibition.

100 Deals associated with Cariporide mesilate

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Angina, Unstable	Phase 2	-	-	-
Angina, Unstable	Phase 2	DE	Aventis SA	-
Angina, Unstable	Phase 2	-	Sanofi	-
Arrhythmias, Cardiac	Phase 2	DE	Aventis SA	-
Myocardial Infarction	Phase 2	-	Sanofi	-
Myocardial Infarction	Phase 2	-	-	-
Myocardial Infarction	Phase 2	DE	Aventis SA	-
Colorectal Cancer	Preclinical	US	Brown University	01 Jul 2021

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