胰腺导管腺癌（PDAC）仍然是最致命的癌症类型。 PDAC 的特点是纤维化、缺氧和可能呈酸性的肿瘤微环境 (TME)。酸性 TME 在肿瘤的发生、进展、侵袭性和化疗耐药性中发挥着重要作用。导管离子转运蛋白/通道的失调可能导致细胞外 pH (pHe) 酸化和 PDAC 进展。我们的目的是测试 H /K -ATP 酶和 pH 敏感的 K 通道是否有助于这些过程，并且可以作为临床批准药物的靶点。我们使用适应各种 pHe 条件并以单层和球体形式生长的人类胰腺癌细胞。首先，我们创建了在外质膜表达 pHoran4 的细胞，并表明泮托拉唑（H /K -ATP 酶抑制剂）可碱化 pHe。其次，我们使用 FluoVolt 监测膜电压 (Vm)，结果表明利鲁唑超极化 Vm，很可能是通过打开 pH 敏感 K 通道（如 TREK-1）实现的。第三，我们发现泮托拉唑和利鲁唑可抑制适应各种 pHe 条件的癌细胞单层和球体的细胞增殖和活力。最重要的是，两种药物联合使用对 PDAC 细胞存活具有显着更大的抑制作用。我们提出，通过重新利用泮托拉唑和利鲁唑来共同靶向 H /K -ATP 酶和 pH 敏感 K 通道，可以提供 PDAC 的新型酸中毒靶向疗法。© 2024 作者。约翰·威利出版的《国际癌症杂志》

Pancreatic ductal adenocarcinoma (PDAC) remains the most lethal cancer type. 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 (pHe) acidification and PDAC progression. Our aim was to test whether H+/K+-ATPases and pH-sensitive K+ channels contribute to these processes and could be targeted by clinically approved drugs. We used human pancreatic cancer cells adapted to various pHe conditions and grown in monolayers and spheroids. First, we created cells expressing pHoran4 at the outer plasma membrane and showed that pantoprazole, the H+/K+-ATPase inhibitor, alkalinized pHe. Second, we used FluoVolt to monitor the membrane voltage (Vm) and showed that riluzole hyperpolarized Vm, most likely by opening of pH-sensitive K+ channels such as TREK-1. Third, we show that pantoprazole and riluzole inhibited cell proliferation and viability of monolayers and spheroids of cancer cells adapted to various pHe conditions. Most importantly, combination of the two drugs had significantly larger inhibitory effects on PDAC cell survival. We propose that co-targeting H+/K+-ATPases and pH-sensitive K+ channels by re-purposing of pantoprazole and riluzole could provide novel acidosis-targeted therapies of PDAC.© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.