Cinnamic acid enhances vinorelbine-induced cytotoxicity in MDA-MB-231 cells through modulation of PTEN and ATG5 expression.

The purpose of this study was to investigate the potential synergistic effects of cinnamic acid (CA) and vinorelbine (VNR) on cytotoxicity in triple-negative breast cancer, aiming to develop new therapeutic strategies targeting specific molecular pathways. The cytotoxic effects of VNR and CA on the human triple-negative breast cancer cell line MDA-MB-231 was investigated from January 15 to October 25, 2024, using in vitro assays and molecular techniques. Cell proliferation and viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay, while drug combination efficacy was assessed using Synergy Finder 3.0 software. Morphological changes and gene expression changes were evaluated post-treatment, and quantitative real-time polymerase chain reaction was used to analyze gene expression changes in response to drug exposure. The combination of VNR and CA significantly reduced cell viability, with IC₅₀ values of 142.6 nM and 4.3 mM, respectively. The combination led to a significant increase in cell death compared to either agent alone (P < .0001, VNR + CA group vs VNR or CA group) Morphological analysis showed apoptotic features in cells treated with the combination therapy. VNR treatment significantly decreased phosphatase and tensin homolog (PTEN) expression (P < .01), while CA alone significantly increased PTEN levels (P < .0001). The combination significantly maintained elevated PTEN expression by 10-fold compared with VNR alone (P < .0001). VNR and CA alone did not significantly affect autophagy-related gene 5 expression. Thus, the combination of CA and VNR appears to synergistically enhance cancer cell death by promoting PTEN-mediated apoptotic signaling and autophagy-related gene 5-associated autophagy, suggesting a dual contribution of both pathways to the observed cytotoxicity. SIGNIFICANCE STATEMENT: This study investigated the combined effects of cinnamic acid (CA) and vinorelbine (VNR) on cytotoxicity in MDA-MB-231 triple-negative breast cancer cells. The combination of VNR and CA dramatically lowered cell viability while increasing cell death. Morphological study revealed apoptotic characteristics, and the combination maintained higher PTEN expression than VNR alone. CA amplifies VNR's cytotoxic effects by altering the expression of PTEN and ATG5, likely resulting in increased apoptosis and enhanced autophagy, both contributing to cancer cell death.