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Adenosine signaling, particularly through CD73 and P1 receptors, contributes to tumor progression and immune modulation. Pantoprazole, a proton pump inhibitor widely used in clinical practice, has recently been suggested as a potential modulator of adenosinergic pathways. This study investigated the ability of pantoprazole to modulate adenosine signaling. In silico docking analyses were performed to assess the binding of pantoprazole to adenosine P1 receptors and CD73, followed by in vitro assays using esophageal adenocarcinoma (OE33) and squamous cell carcinoma (KYSE450) cell lines to evaluate cell growth, adenosinergic signaling, and tumor-related cellular functions following pantoprazole treatment. Docking analyses identified CD73 and P1 receptors, particularly A\n                    <jats:sub>2A<\/jats:sub>\n                    , as favorable molecular targets for pantoprazole. Pantoprazole significantly reduced proliferation and metabolic activity in both cell lines in a concentration-dependent manner, with pronounced inhibition of clonogenic survival in adenocarcinoma cells. Pantoprazole altered P1 receptor expression, particularly A\n                    <jats:sub>2A<\/jats:sub>\n                    , and pharmacological antagonism supported the involvement of these receptors in its antiproliferative effects. Additionally, pantoprazole modulated CD73 expression and reduced cell adhesion and MMP\u20112 expression. These findings indicate that pantoprazole exerts antitumor effects by modulating the CD73\u2013adenosine\u2013P1 receptor axis, supporting its potential repurposing as an adjunctive strategy for the treatment of esophageal adenocarcinoma.\n                  <\/jats:p>","DOI":"10.1007\/s00044-026-03618-2","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:30:19Z","timestamp":1790310619000},"page":"2094-2108","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pantoprazole as a potential repurposed drug targeting the adenosinergic system in esophageal cancer"],"prefix":"10.1007","volume":"35","author":[{"given":"Adriana","family":"Simioni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael D","family":"Weimer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia B","family":"de Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isadora V","family":"Citrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia A","family":"da Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaline","family":"Cardoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria E","family":"Delawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis FSM","family":"Timmers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda B","family":"Morrone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"issue":"24","key":"3618_CR1","doi-asserted-by":"publisher","first-page":"3108","DOI":"10.1097\/cm9.0000000000003420","volume":"20","author":"L Qi","year":"2024","unstructured":"Qi L, Sun M, Liu W, Zhang X, Yu Y, Tian Z, Ni Z, Zheng R, Li Y. 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