Pharmacological inhibition of hypoxia induced acidosis employing a CAIX inhibitor sensitizes gemcitabine resistant PDAC cells
Abstract The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is attributed to tumor microenvironment driven by hypoxia regulated carbonic anhydrase IX. Our study elucidates the ability of Methazolamide, a CAIX inhibitor to sensitize resistant PDAC cells. The effect of Methazolamide alone a...
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Nature Portfolio
2025-05-01
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| Online Access: | https://doi.org/10.1038/s41598-025-93388-5 |
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| author | Jeevan Ghosalkar Vinay Sonawane Swati Achrekar Kalpana Joshi |
| author_facet | Jeevan Ghosalkar Vinay Sonawane Swati Achrekar Kalpana Joshi |
| author_sort | Jeevan Ghosalkar |
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| description | Abstract The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is attributed to tumor microenvironment driven by hypoxia regulated carbonic anhydrase IX. Our study elucidates the ability of Methazolamide, a CAIX inhibitor to sensitize resistant PDAC cells. The effect of Methazolamide alone and in combination with gemcitabine on proliferation, migration, tumor inhibition along with its impact on metastasis by influencing HIF-1α/PTEN/Glut1/Glut3 signalling through the expression of CAIX was assessed. Methazolamide induced cytotoxicity in several PDAC cells including patient derived with IC50 0.7–4.09 mM and 0.29–2.56 mM in monolayer and clonogenic assays respectively. Methazolamide alone and in combination significantly downregulated hypoxia induced expression of HIF-1α and CAIX together with proliferation (Ki-67, Cyclin D1), invasion (Rac-1, Snail), stem cell (Oct-4, Sox-2), angiogenesis (VEGF), glycolysis (Glut1, Glut3) and apoptosis (Bax, Bc1-2 and PTEN) markers in MIA PaCa-2 and PANC-1 cells. In vivo study in PAXF 546L PDX model exhibited profound tumor growth inhibition with downregulation of CD34, Oct-4, Sox-2, C-myc, Nanog, Ki-67, and Rac-1 signalling. Considering inadequate availability of effective therapeutics and importance of CAIX in processes leading to aggressive behavior of PDAC, targeting it by using Methazolamide, a pre-approved drug in combination with gemcitabine represents promising therapeutic approach specifically in metastatic settings. |
| format | Article |
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| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
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| spelling | doaj-art-2f5f23c368df437f8ce6654396facef52025-08-20T01:51:31ZengNature PortfolioScientific Reports2045-23222025-05-0115111610.1038/s41598-025-93388-5Pharmacological inhibition of hypoxia induced acidosis employing a CAIX inhibitor sensitizes gemcitabine resistant PDAC cellsJeevan Ghosalkar0Vinay Sonawane1Swati Achrekar2Kalpana Joshi3Discovery Biology Division, Cipla Ltd.Discovery Biology Division, Cipla Ltd.Discovery Biology Division, Cipla Ltd.Discovery Biology Division, Cipla Ltd.Abstract The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is attributed to tumor microenvironment driven by hypoxia regulated carbonic anhydrase IX. Our study elucidates the ability of Methazolamide, a CAIX inhibitor to sensitize resistant PDAC cells. The effect of Methazolamide alone and in combination with gemcitabine on proliferation, migration, tumor inhibition along with its impact on metastasis by influencing HIF-1α/PTEN/Glut1/Glut3 signalling through the expression of CAIX was assessed. Methazolamide induced cytotoxicity in several PDAC cells including patient derived with IC50 0.7–4.09 mM and 0.29–2.56 mM in monolayer and clonogenic assays respectively. Methazolamide alone and in combination significantly downregulated hypoxia induced expression of HIF-1α and CAIX together with proliferation (Ki-67, Cyclin D1), invasion (Rac-1, Snail), stem cell (Oct-4, Sox-2), angiogenesis (VEGF), glycolysis (Glut1, Glut3) and apoptosis (Bax, Bc1-2 and PTEN) markers in MIA PaCa-2 and PANC-1 cells. In vivo study in PAXF 546L PDX model exhibited profound tumor growth inhibition with downregulation of CD34, Oct-4, Sox-2, C-myc, Nanog, Ki-67, and Rac-1 signalling. Considering inadequate availability of effective therapeutics and importance of CAIX in processes leading to aggressive behavior of PDAC, targeting it by using Methazolamide, a pre-approved drug in combination with gemcitabine represents promising therapeutic approach specifically in metastatic settings.https://doi.org/10.1038/s41598-025-93388-5PDACHypoxiaHIF-1αCarbonic anhydraseMethazolamideRepurposing |
| spellingShingle | Jeevan Ghosalkar Vinay Sonawane Swati Achrekar Kalpana Joshi Pharmacological inhibition of hypoxia induced acidosis employing a CAIX inhibitor sensitizes gemcitabine resistant PDAC cells Scientific Reports PDAC Hypoxia HIF-1α Carbonic anhydrase Methazolamide Repurposing |
| title | Pharmacological inhibition of hypoxia induced acidosis employing a CAIX inhibitor sensitizes gemcitabine resistant PDAC cells |
| title_full | Pharmacological inhibition of hypoxia induced acidosis employing a CAIX inhibitor sensitizes gemcitabine resistant PDAC cells |
| title_fullStr | Pharmacological inhibition of hypoxia induced acidosis employing a CAIX inhibitor sensitizes gemcitabine resistant PDAC cells |
| title_full_unstemmed | Pharmacological inhibition of hypoxia induced acidosis employing a CAIX inhibitor sensitizes gemcitabine resistant PDAC cells |
| title_short | Pharmacological inhibition of hypoxia induced acidosis employing a CAIX inhibitor sensitizes gemcitabine resistant PDAC cells |
| title_sort | pharmacological inhibition of hypoxia induced acidosis employing a caix inhibitor sensitizes gemcitabine resistant pdac cells |
| topic | PDAC Hypoxia HIF-1α Carbonic anhydrase Methazolamide Repurposing |
| url | https://doi.org/10.1038/s41598-025-93388-5 |
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