Exportin 1 inhibitor KPT‑330 reverses oxaliplatin resistance via p53 nuclear retention in colorectal cancer

Despite the established clinical efficacy of oxaliplatin in colorectal cancer (CRC), resistance to this platinum‑based agent continues to pose a significant therapeutic challenge. Increased exportin 1 (XPO1) expression in CRC has been linked to chemoresistance, while KPT‑330, a selective XPO1 inhibitor, has exhibited potential in enhancing platinum drug effectiveness in other cancer types. The present study explored the synergistic effects of KPT‑330 and oxaliplatin in oxaliplatin‑resistant CRC models. Oxaliplatin‑resistant cell lines (HCT116/L‑OHP and HCT8/L‑OHP) were developed, exhibiting elevated XPO1 expression as demonstrated by western blotting. A range of <i>in vitro</i> assays (Cell Counting Kit‑8 assays, ethynyldeoxyuridine assays, crystal violet staining, transmission electron microscopy and flow cytometry) and an in vivo subcutaneous xenograft model in nude mice were used to evaluate the combination therapy. Co‑treatment with KPT‑330 and oxaliplatin induced G2/M phase arrest and mitochondrial dysfunction, thereby triggering apoptosis and ferroptosis. Mechanistically, the combination therapy of KPT‑330 and oxaliplatin promoted the nuclear retention of p53, which in turn upregulated p21 and downregulated solute carrier family 7 member 11. <i>In vivo</i>, the combination therapy significantly enhanced tumor sensitivity to oxaliplatin. These results suggested that KPT‑330 restored oxaliplatin sensitivity in resistant CRC by facilitating p53 nuclear retention, presenting a promising approach to overcome chemoresistance through dual modulation of cell cycle arrest and ferroptosis pathways.