Flavonoids and nitrogen-containing heterocyclic phytochemicals regulate DNA repair via mir-2909-mediated modulation of MRN-checkpoint genes in breast cancer.

Dysregulation of DNA damage repair pathways and miRNA-mediated control play crucial targets in breast cancer therapeutics, highlighting the need for novel multi-targeted therapeutic agents. In this study, the druggability properties and biological activity of structurally distinct phytochemicals, Flavonoids (F), and Nitrogen-containing heterocyclic-compounds (N) on the DNA repair checkpoint sensor genes (MRN complex), miR-2909 expression, ROS, and cell cycle analysis in breast cancer cell models (MDA-MB-231 and MCF-7) were investigated and compared against the FDA-approved anticancer agent Palbociclib (P). Both compound classes significantly inhibited breast cancer cell proliferation, with nitrogen-containing heterocyclics showing superior cytotoxicity. Cell Cycle analyses revealed G0-G1 phase arrest upon treatment with N-compounds, while F-compounds induced Sub-G1 enrichment. N-compounds triggered greater ROS levels in the MDA-MB-231 cells than F-compounds, which showed greater ROS levels in MCF-7 cells. Similarly, DNA repair genes expression [MRN complex (MRE11, RAD50, NBN)] and miR-2909 expression analysis revealed greater regulation with N-compounds as compared to F-compounds in a cell type-specific manner, as compared to the FDA-approved anticancer agent Palbociclib. Docking simulations further confirmed compounds high-affinity interactions with MRN-complex proteins and mature miR-2909 over Palbociclib. Detailed analysis of compounds and target druggability properties through ADMET studies reflects their drug-likeness, non-mutagenic, and non-carcinogenic profiles to support their therapeutic potential. These findings suggest that phytochemicals, particularly N-compounds over F-compounds, may exert superior anticancer effects by modulating cell cycle, DNA repair markers, oxidative stress, and miR-2909 networks. This study provides a mechanistic basis and preclinical framework for developing F and N-compounds as epigenetic and genomic modulators in breast cancer.