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PDAC is characterized by fibrotic, hypoxic, and presumably acidic tumor microenvironment (TME). Acidic TME is an important player in tumor development, progression, aggressiveness, and chemoresistance. The dysregulation of ductal ion transporters\/channels might contribute to extracellular pH (pH<jats:sub>e<\/jats:sub>) acidification and PDAC progression. Our aim was to test whether H<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010ATPases and pH\u2010sensitive K<jats:sup>+<\/jats:sup> channels contribute to these processes and could be targeted by clinically approved drugs. We used human pancreatic cancer cells adapted to various pH<jats:sub>e<\/jats:sub> conditions and grown in monolayers and spheroids. First, we created cells expressing pHoran4 at the outer plasma membrane and showed that pantoprazole, the H<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010ATPase inhibitor, alkalinized pH<jats:sub>e<\/jats:sub>. Second, we used FluoVolt to monitor the membrane voltage (<jats:italic>V<\/jats:italic><jats:sub><jats:italic>m<\/jats:italic><\/jats:sub>) and showed that riluzole hyperpolarized <jats:italic>V<\/jats:italic><jats:sub><jats:italic>m<\/jats:italic><\/jats:sub>, most likely by opening of pH\u2010sensitive K<jats:sup>+<\/jats:sup> channels such as TREK\u20101. Third, we show that pantoprazole and riluzole inhibited cell proliferation and viability of monolayers and spheroids of cancer cells adapted to various pH<jats:sub>e<\/jats:sub> conditions. Most importantly, combination of the two drugs had significantly larger inhibitory effects on PDAC cell survival. We propose that co\u2010targeting H<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010ATPases and pH\u2010sensitive K<jats:sup>+<\/jats:sup> channels by re\u2010purposing of pantoprazole and riluzole could provide novel acidosis\u2010targeted therapies of PDAC.<\/jats:p>","DOI":"10.1002\/ijc.35076","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T13:53:42Z","timestamp":1720446822000},"page":"1641-1654","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pantoprazole and riluzole target H<sup>+<\/sup>\/K<sup>+<\/sup>\u2010<scp>ATPases<\/scp> and <scp>pH<\/scp>\u2010sensitive K<sup>+<\/sup> channels in pancreatic cancer cells"],"prefix":"10.1002","volume":"155","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7295-8731","authenticated-orcid":false,"given":"Ganga","family":"Deshar","sequence":"first","affiliation":[{"name":"Department of Biology University of Copenhagen  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