Lutein Influences Cisplatin Sensitivity Through Differential Regulation of DNA Damage Response Genes in Breast Cancer...

This study investigated the effects of lutein, a natural carotenoid, and the chemotherapeutic agent cisplatin on three cell lines: HUVEC (non-cancerous), MDA-MB-231 (ER- breast cancer), and MCF-7 (ER+ breast cancer). Cells were treated with lutein, cisplatin, or both for 24 and 48 h. Cell viability was evaluated using the MTT assay; oxidative DNA damage was assessed via 8-OHdG levels; apoptosis was determined by caspase-3 protein level; and DNA damage response (DDR) gene expression was analyzed through real-time PCR. Lutein exhibited time- and cell type-dependent cytotoxicity. It significantly reduced viability in MDA-MB-231 cells and showed a mild effect in MCF-7 cells, while in HUVECs, cytotoxicity was more evident in the combination group. Lutein elevated oxidative DNA damage in cancer cells but had minimal effect in HUVECs; this pro-oxidant activity persisted in combination with cisplatin. Caspase-3 level was notably increased in MDA-MB-231 cells, correlating with cell death. At the gene expression level, cisplatin consistently upregulated DDR genes, while lutein exerted suppressive or variable effects depending on the gene and cell type. In MCF-7 cells, lutein downregulated key repair genes such as BRCA1, XRCC1 and XRCC6, while its combination with cisplatin notably upregulated ATM and RAD51, suggesting potential synergistic interaction through modulation of estrogen-related DNA repair. In contrast, MDA-MB-231 cells displayed increased DDR gene expression following combination treatment, indicating a possible reduction in cisplatin sensitivity. Synergy analysis revealed that the interaction between lutein and cisplatin was largely additive in MDA-MB-231 cells, mildly synergistic in HUVECs, and highly variable in MCF-7 cells, ranging from synergistic to antagonistic responses. Overall, these findings suggest that lutein modulates DNA repair pathways in a cell-specific manner and may alter the efficacy of chemotherapeutic regimens depending on the hormonal and genetic background of the tumor.