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• W2100038753 abstract "Abstract Purpose: The purpose of this study was to assess whether troglitazone (TRO) would induce cellular acidosis by inhibiting Na+/H+ exchanger (NHE) 1 in breast carcinoma-derived cell lines and, if so, whether cellular acidosis would be associated with a reduction in proliferation. Experimental Design: Intracellular pH (pHi) and acid extrusion capacity after an exogenous acid load were assayed using (2, 7)-biscarboxyethyl-5(6)-carboxyfluorescein in MCF-7 and MDA-MB-231 cells treated with TRO. Radiolabeled thymidine incorporation was used to assess DNA synthesis. Peroxisome proliferator-activated receptor (PPAR) γ involvement was assessed using an antagonist and PPARγ−/− NIH3T3 cells. Results: TRO induced a prompt (&lt;4 minute) and severe cellular acidosis in both MCF-7 (7.54 ± 0.23 to 6.77 ± 0.06; P &lt; 0.001) and MDA-MB-231 cells (7.38 ± 0.18 to 6.89 ± 0.25; P &lt; 0.05) after 12 minutes, without increasing acid production. Acid extrusion as assessed by the response to an exogenous acid load (NH4Cl pulse) was markedly blunted (MDA-MB-231, P &lt; 0.01) or eliminated (MCF-7, P &lt; 0.001). Chronic exposure to TRO resulted in NHE1 activity reduction (P &lt; 0.05) and a dose-dependent decrease in DNA synthesis (&lt;75% inhibition at 100 μmol/L; P &lt; 0.001 and P &lt; 0.01 for MCF-7 and MDA-MB-231, respectively) associated with a decreased number of viable cells. TRO-mediated inhibition of proliferation was not reversed by the presence of the PPARγ inhibitor GW9662 and was demonstrable in PPARγ−/− NIH3T3 cells, consistent with a PPARγ-independent mechanism. Conclusions: TRO induces marked cellular acidosis in MCF-7 and MDA-MD-231 cells. Sustained acidosis is consonant with decreased proliferation and growth that is not reversed by a PPARγ antagonist. Our results support a NHE-mediated action of TRO that exerts its effect independent of PPARγ." @default.
• W2100038753 created "2016-06-24" @default.
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• W2100038753 date "2004-10-15" @default.
• W2100038753 modified "2023-09-23" @default.
• W2100038753 title "Troglitazone Acts on Cellular pH and DNA Synthesis through a Peroxisome Proliferator-Activated Receptor γ-Independent Mechanism in Breast Cancer-Derived Cell Lines" @default.
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• W2100038753 doi "https://doi.org/10.1158/1078-0432.ccr-04-0879" @default.
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