Flavopiridol inhibits FOXM1/NF-kB and KRAS/MAPK signaling and DNA repair mechanims and Sensitizes Triple-Negative Breast Cancer Cells to Doxorubicin the

Abstract Purpose Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by frequent chemoresistance and poor clinical outcomes. Doxorubicin (DOX) is a standard therapeutic agent; however, acquired resistance limits its efficacy. Forkhead box M1 (FOXM1) and nuclear factor-κB (NF-κB) are key regulators of pro-survival signaling pathways implicated in TNBC progression and drug resistance. This study aimed to investigate whether flavopiridol enhances DOX sensitivity in TNBC cells by targeting the FOXM1–NF-κB signaling axis. Methods MDA-MB-231 and BT-549 TNBC cell lines were treated with DOX, flavopiridol, or their combination. Cell viability, clonogenic survival, apoptosis, and cell-cycle distribution were assessed. Protein expression levels of FOXM1, NF-κB, RAS/MAPK, and PARP were analyzed by Western blot. FOXM1 function was further evaluated באמצעות siRNA-mediated gene silencing. Results Combination treatment significantly reduced cell viability and clonogenic potential compared to single-agent treatments. Flavopiridol enhanced DOX-induced apoptosis and induced marked alterations in cell-cycle progression in both TNBC cell lines. At the molecular level, combination therapy suppressed FOXM1 expression and downregulated NF-κB and RAS/MAPK signaling pathways. FOXM1 silencing recapitulated these effects, confirming its central role in pro-survival signaling. Additionally, decreased PARP expression suggested impaired DNA repair capacity. Conclusion The FOXM1–NF-κB–RAS/MAPK axis plays a critical role in DOX resistance in TNBC. Targeting FOXM1 with flavopiridol enhances DOX sensitivity and represents a promising therapeutic strategy to overcome chemoresistance in aggressive TNBC.