biostudies-literatureUnknown35Son AIntrinsic or acquired radioresistance often limits the efficacy of radiation therapy (RT), thereby leading to local control failure. Cancerous cells have abnormal pH dynamics due to high metabolic demands, but it is unclear how pH dynamics contribute to radioresistance. In this study, we investigated the role of Na-H exchange 1 (NHE1), the major intracellular pH (pH_i) regulator, in RT response. We observed that RT increased NHE1 expression and modulated pH_i in MDA-MB-231 human breast cancer cells. When combined with RT, pharmacological NHE1 inhibition by 5-(N-Ethyl-N-isopropyl)amiloride (EIPA) reduced pH_i and clonogenic survival. EIPA attenuated radiation-damaged DNA repair, increasing G2/M cell cycle arrest. The combination of EIPA and RT increased apoptotNeoplasia (New York, N.Y.)100862https://www.ebi.ac.uk/biostudies/studies/S-EPMC9761853biostudies-literatureTargeting Na-H exchanger 1 overcomes nuclear factor kappa B-mediated tumor resistance to radiotherapy.PMC9761853Choi SChoi CKim WSon AKang SKim YShin SWfalseTargeting Na-H exchanger 1 overcomes nuclear factor kappa B-mediated tumor resistance to radiotherapy.Intrinsic or acquired radioresistance often limits the efficacy of radiation therapy (RT), thereby leading to local control failure. Cancerous cells have abnormal pH dynamics due to high metabolic demands, but it is unclear how pH dynamics contribute to radioresistance. In this study, we investigated the role of Na-H exchange 1 (NHE1), the major intracellular pH (pH_i) regulator, in RT response. We observed that RT increased NHE1 expression and modulated pH_i in MDA-MB-231 human breast cancer cells. When combined with RT, pharmacological NHE1 inhibition by 5-(N-Ethyl-N-isopropyl)amiloride (EIPA) reduced pH_i and clonogenic survival. EIPA attenuated radiation-damaged DNA repair, increasing G2/M cell cycle arrest. The combination of EIPA and RT increased apoptot2023-01-01T00:00:00Z2023 Jan2025-04-26T09:49:54.021Z2025-04-06T13:07:54.395ZS-EPMC97618533650887610.1016/j.neo.2022.100862