Quercetin Attenuates Cisplatin-Induced Nephrotoxicity While Enhancing Antitumor Efficacy in Gastric Cancer via Cell Type-Specific Modulation of the ERK1/2 Pathway.

Cisplatin (DDP) is a cornerstone chemotherapeutic agent for gastric cancer, yet its clinical application is often limited by severe adverse effects, particularly dose-dependent nephrotoxicity. Quercetin (Que) is a dietary flavonoid widely present in everyday foods such as onions, apples, tea, and broccoli. It has been reported to possess both renoprotective and antitumor properties. This study evaluated the therapeutic potential of combining DDP with Que in gastric cancer treatment. In vitro, CCK-8 assays, flow cytometry, and scratch wound tests were employed to assess the impact of Que on DDP-induced nephrotoxicity and chemosensitivity, while potential mechanisms were investigated through western blot analysis. In vivo, the combined regimen was tested in tumor-bearing nude mice by monitoring tumor growth and renal function. Our results showed that Que alleviated DDP-induced suppression of proliferation and apoptosis in HK-2 cells, indicating protection against nephrotoxicity. In comparison, in AGS gastric cancer cells, Que potentiated DDP-induced inhibition of proliferation and migration, and improved apoptosis. Mechanistically, Que inhibited ERK1/2 activation in both cell types. In HK-2 cells, ERK1/2 inhibition increased c-Myc expression and decreased cleaved caspase-3 levels, whereas in AGS cells, ERK1/2 inhibition reduced c-Myc and MMP-2 levels while elevating cleaved caspase-3 expression. These effects were reversed upon TBHQ treatment. In vivo, Que enhanced the antitumor efficacy of DDP while attenuating its nephrotoxicity. Collectively, these results indicate that Que achieves the abovementioned dual effect via cell type-specific modulation of the ERK1/2 pathway, supporting its potential as an adjuvant for gastric cancer chemotherapy.