Work

Ellagic acid promoted efficacy of oxaliplatin on wild-type TP53 colorectal cancer via regulating ataxia-telangiectasia mutated protein kinase and Wip1

Year: 2026

Type: article

Abstract: Introduction Drug resistance in colorectal cancer frequently leads to chemotherapy failure. The application of small-molecule compounds to enhance chemotherapy efficacy has become a common therapeutic strategy. Ellagic acid, a natural polyphenol in plants, is abundantly contained in herbal medicines used for adjuvant chemotherapy against colorectal cancer. Nevertheless, the regulatory effect of ellagic acid on oxaliplatin-based chemotherapy remains unclear. Methods Cell Counting Kit-8 and colony formation assays were used to evaluate the efffcacy of the combination of ellagic acid and oxaliplatin. Network pharmacology, Human Phospho-Kinase Array, co-immunoprecipitation and thermal shift assay were used to screen potential targets of ellagic acid in chemotherapy sensitization. Transfection of overexpression plasmids and shRNAs against these targets was performed to verify the underlying mechanism. Tumor tissues derived from colorectal cancer patients were used to establish PDX models for in vivo experiments. All cells and tissues used in this study have wild-type TP53 . Results Cellular experiments demonstrated that ellagic acid exerts a synergistic effect with oxaliplatin. Target screening revealed that ellagic acid inhibits Wip1, thereby upregulating p53 and resulting in the synergistic anti-tumor effect. Further studies demonstrated that ellagic acid interacts to ATM and suppresses ATM phosphorylation, thereby downregulating Wip1 via the ATM/ AMPK/HIPK2 signaling pathway. Data from FOLFOX chemotherapy indicated that high Wip1 expression correlates with poor prognosis. PDX models demonstrated that ellagic acid enhances the therapeutic efficacy of oxaliplatin, particularly in tumors with high Wip1 expression. Discussion Our findings indicate that ellagic acid enhances the antitumor efficacy of oxaliplatin in colorectal cancer with wild-type TP53 and high Wip1 expression.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1944826