Cold atmospheric plasma restores fulvestrant sensitivity by inhibiting CCND3 in the drug-resistant breast cancer cells

Abstract

Cold atmospheric plasma (CAP) has demonstrated anti-proliferative activity in various cancer cells, yet its efficacy against drug-resistant cancer cells remains largely unexplored. This study investigates CAP’s potential to restore drug sensitivity in fulvestrant-resistant breast cancer cells. Fulvestrant-resistant T47D/fulR and MCF-7/fulR cell lines were developed through 32-week drug exposure. CAP treatment effectively inhibited growth of both resistant cell lines and restored sensitivity to fulvestrant when used as pretreatment. Genome-wide expression analysis revealed that CAP significantly impacts ribosomal and mitochondrial components during resistance acquisition and treatment. The oncogene CCND3 emerged as a key contributor to drug resistance, being highly upregulated in resistant cells but downregulated following CAP treatment. Functional validation through CCND3 knockdown in both resistant cell lines induced increased apoptosis and extended G1 phase, confirming its critical role in resistance mechanisms. These findings demonstrate that CAP can revert fulvestrant-resistant breast cancer cells to a sensitive state by targeting CCND3 and modulating critical cellular pathways, suggesting promising therapeutic potential for overcoming drug resistance in breast cancer treatment. © 2025 Elsevier B.V., All rights reserved.