Epigallocatechin gallate overcomes oxaliplatin resistance in colorectal cancer by suppressing NF-κB signaling and disrupting mitochondrial homeostasis.

BACKGROUND

Acquired resistance to oxaliplatin remains a major obstacle to the successful treatment of advanced colorectal cancer, highlighting the necessity for the development of novel strategies for restoring chemosensitivity. Epigallocatechin-3-gallate (EGCG), the principal polyphenol of green tea, exhibits diverse anticancer activities. This study investigated the efficacy of EGCG against oxaliplatin-resistant colorectal cancer cells, with particular emphasis on mitochondrial bioenergetics and NF-κB signaling.

METHODS

Oxaliplatin-resistant HT-29, HCT116, and SW480 colorectal cancer cell lines were established through stepwise drug selection. Cell viability, colony formation, cell-cycle distribution, apoptosis, mitochondrial respiration, intracellular ATP production, gene expression assays, and xenograft models were employed to characterize the effects of EGCG.

RESULTS

EGCG markedly restored oxaliplatin sensitivity in resistant colorectal cancer cells, significantly reducing cell viability and clonogenic capacity along with the induction of G2/M arrest and apoptosis. EGCG profoundly impaired mitochondrial bioenergetics by suppressing oxidative phosphorylation, glycolytic capacity, and ATP production. EGCG inhibited NF-κB activation and downregulated mitochondrial metabolic genes. Restoration of mitochondrial function by PGC1α overexpression partially reversed these effects, whereas concurrent activation of NF-κB signaling with TNF-α caused a more robust rescue, demonstrating a convergence between mitochondrial metabolism and NF-κB signaling in contributing to the resistant phenotype. Besides, EGCG significantly suppressed tumor growth and prolonged survival in oxaliplatin-resistant colorectal cancer xenografts.

CONCLUSIONS

EGCG helped overcome oxaliplatin resistance by promoting apoptosis and inhibiting tumor progression through disruption of mitochondrial bioenergetics and suppression of NF-κB signaling.