Harnessing Natural Products to Surmount Drug Resistance in Gastric Cancer: Mechanisms and Therapeutic Perspectives

Gastric cancer remains a major cause of mortality. The current standard of care of gastric cancer is based upon combination chemotherapy comprising platinum, fluoropyrimidines drugs and docetaxel. However, the efficacy of chemotherapy is hindered by intrinsic and acquired drug resistance, resulting in poor patient prognosis. Studies are currently exploring the potential of immunotherapy and other biologically targeted agents in the perioperative setting. To select the most efficacious therapy for advanced gastric cancer, including adenocarcinoma of the esophago-gastric junction, it is essential to determine key biomarkers including for example human epidermal growth factor receptor 2 (HER2) expression, programmed death-ligand 1 (PD-L1) combined positive score (CPS), Claudin 18.2, and microsatellite instability (MSI). Moreover, recent studies have highlighted the potential of natural products as effective agents in surmounting anticancer drug resistance in gastric cancer. These bioactive compounds exhibit various antitumor activities, including induction of apoptosis, inhibition of cell proliferation, modulation of autophagy, and most importantly reversal of distinct multidrug resistance (MDR) modalities. The present review provides a comprehensive analysis of the mechanisms underlying chemoresistance in gastric cancer and explores how natural products can overcome distinct MDR mechanisms. We further discuss the therapeutic potential of combining natural products with established chemotherapeutics and immunotherapy agents to enhance treatment efficacy and reduce adverse effects.