Journal of Biological Chemistry

5-Fluorouracil (5-FU) is a commonly used chemotherapeutic agent for breast cancer. Its efficacy relies on the function of p53, and mutations in p53 contribute to the development of resistance during 5-FU chemotherapy. Here, we report that microcurrent stimulation (MCS) of a p53-mutant breast cancer cell line induces p53-mediated cell death. Although MDA-MB-231 and MDA-MB-468 cells, both human breast cancer cell lines, are less sensitive to 5-FU due to p53 mutations, MCS (300 μA for 30 min) induced apoptosis in these cells and improved the antitumor effect of 5-FU in tumor-bearing mice. MCS-induced apoptosis was mediated by an increase in intracellular Cu2+ ions and reactive oxygen species, along with the concurrent transcriptional enhancement of pro-apoptotic genes by p53. Furthermore, MCS induced apoptosis in MDA-MB-231 cells that had developed resistance to 5-FU and inhibited tumor growth in tumor-bearing mice with reduced 5-FU sensitivity. These findings suggest that an approach involving MCS could serve as a foundation for developing breast cancer treatment strategies to overcome p53 mutations.

5-fluorouracil

chemoresistance

MDA-MB-231 cells

p53

microcurrent

breast cancer

cell death

flow cytometry

apoptosis

reactive oxygen species (ROS)

Aldehyde dehydrogenase

Animal Research, Reporting of In Vivo Experiments

Adenosine triphosphate

3,3′-diaminobenzidine

2′,7′-dichlorodihydrofluorescein diacetate

Dulbecco’s modified eagle medium

Ethylenediaminetetraacetic acid

Human epidermal growth factor receptor 2

Inductively coupled plasma mass spectrometry

Microcurrent stimulation

Phosphate-buffered saline

Pathologic complete response

Radioimmunoprecipitation assay

Reactive oxygen species

Research resource identifier

Sodium dodecyl sulfate

Cu/Zn superoxide dismutase

Tumor-associated macrophages

Triple-negative breast cancer

© 2025 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biologyé