Antitumor Potential of Epigallocatechin Gallate in Overcoming Molecular Therapy Resistance in Hepatocellular Carcinoma

Background/Aim: Epigallocatechin gallate (EGCG), a major green tea polyphenol with anticancer properties, has not been studied in the context of drug-resistant hepatocellular carcinoma (HCC). This study evaluated EGCG's antitumor effects in wild-type Hep3B cells and in lenvatinib- (Hep3BLR) and sorafenib-resistant (Hep3BSR) Hep3B sublines. Materials and Methods: Drug-resistant Hep3B cells were developed through stepwise exposure to lenvatinib or sorafenib. The antiproliferative and pro-apoptotic effects of EGCG (10 μg/ml) were assessed using CCK-8 and ELISA assays, respectively. Protein arrays profiled apoptosis-related molecules, receptor tyrosine kinases (RTKs), and angiogenesis factors. miRNA expression was analyzed using microarray profiling. Functional validation of miR-575 was conducted in nude mouse xenografts. Results: EGCG significantly reduced cell proliferation and induced apoptosis in all cell lines. It down-regulated paraoxonase-2 (PON2) and heat shock protein 27 (HSP27), which were elevated in drug-resistant cells. EGCG also suppressed EGFR expression, especially in Hep3BLR. miRNA profiling revealed differential expression across sublines, with miR-575 consistently up-regulated by EGCG. In vivo, miR-575 mimics significantly reduced tumor volume in wild-type and Hep3BLR xenografts but not in Hep3BSR. Analysis of The Cancer Genome Atlas (TCGA) data showed that low miR-575 and high miR-483-3p expression were associated with poor overall survival in HCC patients. Conclusion: EGCG effectively counters resistance to molecular therapies in HCC by modulating stress-response proteins, RTK signaling, and miRNA profiles. miR-575 appears to mediate its antitumor activity, suggesting potential therapeutic value for EGCG and miR-575–based strategies in treating resistant HCC.