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Background: Paclitaxel (PTX) has been used as a chemotherapeutic agent for several malignancies, including breast cancer, and efforts to increase the efficiency of PTX are continuous. Previous studies have shown that the voltage-gated K + channels are over-expressed in breast cancer cell lines; therefore, blocking this type of K + channel reduces cell proliferation and viability., Aims: In this study, FDA-approved 4-aminopyridine (4-AP), a voltage-gated potassium channel blocker, was used in combination with PTX to improve the anticancer activity of PTX in MCF-7 and MDA-MB-231 cell lines., Methods and Results: Viability was determined with trypan blue, a clonogenic assay was performed, and the cell cycle was determined with a flow cytometer and immunochemistry. To gain an insight into the mechanism, intracellular K + concentration, intracellular Ca 2+ (calcium) concentration, and transmembrane potential measurements were made with corresponding fluorescent dyes. The apoptotic cell number was determined using Annexin /PI method by flow cytometer. Viability decreased with combination therapy and the clonogenic assay proved decreased colony formation. The apoptotic cell number was increased after treatment with the combination in both cell lines. Cell cycle measurements showed G 1 arrest for both MCF-7 and MDA-MB-231 cell lines upon 4-AP treatment. PTX caused G 1 arrest in MCF-7 cells and S phase arrest in MDA-MB-231 cells. Combination treatment caused S phase arrest in MCF-7 cells and S phase and G 2 /M phase arrest in MDA-MB-231 cells. Intracellular K + concentration was increased after all treatments in both cell lines. Ca 2+ concentration was increased significantly after combination treatment. Depolarization in the transmembrane potential was observed after all treatments in both cell lines., Conclusion: Biophysical parameters like the transmembrane potential and ion fluxes have been defined in cancer progression which can provide new aspects for cancer treatments. This study shows that the combination of 4-AP with PTX is a promising alternative the mechanism of which needs further investigation considering the results obtained for Ca 2+ , K + , and membrane potential., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)