Nisin synergizes with doxorubicin, enhancing breast cancer cell apoptosis and DNA damage via membrane permeabilization.
Background
Despite advancements, breast cancer remains a leading cause of death, necessitating more effective therapeutic strategies with novel modes of action. Conventional chemotherapies often face limitations due to side effects and resistance. Combination therapy is a promising approach to enhance drug efficacy and overcome these challenges. Nisin, a cationic antimicrobial peptide, has shown cytotoxicity against various cancer cell lines, primarily through membrane disruption, by preferentially binding to negatively charged phospholipids and forming pores. This study investigates nisin's ability to modulate membrane permeability and its synergistic potential with doxorubicin against breast cancer.
Study Design
Researchers investigated nisin's membrane permeabilization using a liposomal leakage assay with anionic lipids. The anticancer activity of nisin and doxorubicin (DOX) was assessed against MCF-7 and MDA-MB-231 breast cancer cell lines via MTT assay. Synergistic effects were determined using Bliss independence analysis. Cells were treated with 10 µM nisin and 1 µM DOX for 24-48 h. Further mechanisms were explored using fluorescent-based high-content analysis to observe membrane permeability and DOX-induced DNA damage, and flow cytometry with Annexin-V staining to quantify apoptosis.
Results
Nisin demonstrated selective cytotoxicity against breast cancer cells, with IC50 values of 5-8 µM for MCF-7 and MDA-MB-231, while exhibiting lower toxicity towards normal cells. The liposomal leakage assay confirmed nisin's preferential membrane permeabilization with anionic lipids. Bliss independence analysis revealed a marked synergistic effect between nisin and DOX in MCF-7 cells when co-treated with 10 µM nisin and 1 µM DOX for 24-48 h. Fluorescent-based high-content analysis clearly showed that nisin increased cell membrane permeability and promoted DOX-induced DNA damage in both cell lines. Flow cytometry with Annexin-V staining further demonstrated that:
Co-treatment of nisin and DOX significantly enhanced apoptosis compared to individual treatments, particularly in MCF-7 cells, suggesting a key mechanism for their synergistic anticancer activity.
Key Findings
- Nisin exhibited selective cytotoxicity against MCF-7 and MDA-MB-231 breast cancer cells with
IC50values of 5-8 µM. - Nisin preferentially permeabilized anionic lipid membranes, confirming its membrane-disrupting mechanism.
- A synergistic anticancer effect was observed between 10 µM nisin and 1 µM DOX in MCF-7 cells after 24-48 h.
- Nisin increased cell membrane permeability and promoted DOX-induced DNA damage in both breast cancer cell lines.
- Co-treatment with nisin and DOX significantly enhanced apoptosis compared to single treatments, especially in MCF-7 cells.
Why It Matters
This study highlights a novel strategy for enhancing breast cancer therapy by combining nisin with doxorubicin, potentially allowing for lower DOX doses and reduced systemic toxicity. The findings suggest that nisin's membrane-modulating properties could be leveraged to improve the intracellular delivery and efficacy of conventional chemotherapeutics. This combination could offer a new therapeutic approach for breast cancer, particularly for patients where current treatments are suboptimal or resistance is a concern. While currently an in-vitro finding, it lays groundwork for preclinical animal studies to validate efficacy and safety, moving towards a potentially translatable protocol for clinical use.
nisin
doxorubicin
breast-cancer
mcf-7
mda-mb-231
membrane-permeability