乳腺癌组织对细胞内酸化的防御依赖于通过Na ,HCO3-协同转运蛋白NBCn1/Slc4a7和Na /H-交换蛋白NHE1/Slc9a1的净酸排出。 NBCn1 越来越被认为是乳腺癌易感蛋白和有希望的治疗靶点，而针对 NHE1 的证据却不一致。目前，存在针对 NHE1 的选择性小分子抑制剂，但不存在针对 NBCn1 的选择性小分子抑制剂。细胞检测（存在一些差异）将 NHE1 活性与增殖、迁移和侵袭联系起来；破坏 NHE1 表达可以减少三阴性乳腺癌的生长。对人类乳腺癌组织的研究表明，NHE1 高表达与转移减少以及某些分子亚型中患者生存率的提高相关。在这里，我们评估了 NHE1 抑制剂 cariporide/HOE-642 在小鼠 ErbB2 驱动的乳腺癌中的 Na /H 交换和治疗潜力。离体时，cariporide 可抑制乳腺癌组织中的净酸排出 (IC50 = 0.18 μM)，并导致稳态细胞内 pH (pHi) 小幅下降。在体内，我们通过渗透微型泵以及瘤内和瘤周注射口服递送卡立波利，以解决口服生物利用度低和代谢快的问题。体内延长卡立波利给药可上调 NBCn1 表达，将 pHi 调节转向 CO2/HCO3 依赖性机制，并且对 ErbB2 驱动的原发性乳腺癌的生长速率没有显示出净影响。卡立波利也不影响乳腺癌组织中的增殖标志物。口服（而非肠胃外）卡立泊莱可使血糖升高约 1.5 mM。总之，体外急性施用卡立波利可有效抑制乳腺癌组织中的净酸排出，但最低限度地降低稳态 pHi。体内延长卡立波利给药可通过 NBCn1 进行补偿，我们观察到对 ErbB2 驱动的乳腺癌生长没有明显影响。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Defense against intracellular acidification of breast cancer tissue depends on net acid extrusion via Na+,HCO3--cotransporter NBCn1/Slc4a7 and Na+/H+-exchanger NHE1/Slc9a1. NBCn1 is increasingly recognized as breast cancer susceptibility protein and promising therapeutic target, whereas evidence for targeting NHE1 is discordant. Currently, selective small molecule inhibitors exist against NHE1 but not NBCn1. Cellular assays-with some discrepancies-link NHE1 activity to proliferation, migration, and invasion; and disrupted NHE1 expression can reduce triple-negative breast cancer growth. Studies on human breast cancer tissue associate high NHE1 expression with reduced metastasis and-in some molecular subtypes-improved patient survival. Here, we evaluate Na+/H+-exchange and therapeutic potential of the NHE1 inhibitor cariporide/HOE-642 in murine ErbB2-driven breast cancer. Ex vivo, cariporide inhibits net acid extrusion in breast cancer tissue (IC50 = 0.18 μM) and causes small decreases in steady-state intracellular pH (pHi). In vivo, we deliver cariporide orally, by osmotic minipumps, and by intra- and peritumoral injections to address the low oral bioavailability and fast metabolism. Prolonged cariporide administration in vivo upregulates NBCn1 expression, shifts pHi regulation towards CO2/HCO3--dependent mechanisms, and shows no net effect on the growth rate of ErbB2-driven primary breast carcinomas. Cariporide also does not influence proliferation markers in breast cancer tissue. Oral, but not parenteral, cariporide elevates serum glucose by ∼1.5 mM. In conclusion, acute administration of cariporide ex vivo powerfully inhibits net acid extrusion from breast cancer tissue but lowers steady-state pHi minimally. Prolonged cariporide administration in vivo is compensated via NBCn1 and we observe no discernible effect on growth of ErbB2-driven breast carcinomas.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.