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Renal cancer remains a major global health burden, and current targeted and immunotherapeutic strategies are frequently limited by toxicity, therapeutic resistance, and suboptimal response rates. Natural bioactive compounds such as epigallocatechin gallate (EGCG) and cafestol exhibit anticancer activity; however, their therapeutic utility is constrained by limited potency and dose-dependent adverse effects. In this study, the antiproliferative and synergistic effects of cafestol and a hyaluronic acid (HA)–EGCG conjugate were investigated in renal cancer cells. HA conjugation significantly enhanced the antiproliferative efficacy of EGCG in both ACHN and A498 human renal cancer cells, whereas unmodified HA exhibited no intrinsic anticancer activity. Importantly, the HA–EGCG conjugate enabled a pronounced synergistic interaction with cafestol, particularly in ACHN cells, as confirmed by combination index analysis, while free EGCG and cafestol failed to achieve synergistic inhibition. In addition, the HA–EGCG conjugate and its combination with cafestol exhibited favorable selectivity toward renal cancer cells compared with normal renal proximal tubule epithelial cells (RPTECs). This combination robustly enhanced apoptosis and was associated with significant downregulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL at the transcriptional level, together with suppression of the epithelial–mesenchymal transition-associated transcription factor SNAIL at both transcriptional and protein levels. Notably, the enhanced antiproliferative effects were achieved at reduced concentrations, highlighting the potential to mitigate dose-related toxicity. Collectively, these findings support HA-based conjugation as an effective strategy to potentiate the anticancer activity of natural bioactive compounds and to enable synergistic, multi-targeted therapeutic effects against renal cancer.
Yongvongsoontorn et al. (Fri,) studied this question.