Ganoderma lucidum extract reverses multidrug resistance in breast cancer cells through inhibiting ATPase activity of the P-glycoprotein via MAPK/ERK signaling pathway

Breast cancer represents a persistent global health challenge, with multidrug resistance (MDR) posing a significant obstacle to effective treatment. In this study, we investigate the potential of Ganoderma lucidum extract (GLE) in reversing MDR in breast cancer and delve into the underlying mechanisms. We establish a robust in vitro 3D model of breast cancer with acquired MDR induced by paclitaxel. Utilizing the CCK-8 method, we assess the impact of GLE on cytotoxic drug sensitivity to determine its in vitro MDR reversal activity. Our results reveal that GLE enhances the toxicity of paclitaxel in breast cancer cells by inhibiting the ATPase activity of P-glycoprotein (P-gp) and increasing the intracellular and extracellular excretion of P-gp substrates, all without significantly altering P-gp protein expression. Additionally, GLE inhibits the phosphorylation of ERK1/2, suggesting that the enhanced sensitivity of breast cancer cells to paclitaxel by GLE is associated with the MAPK pathway. These findings indicate that GLE may inhibit P-gp-mediated drug efflux via the MAPK pathway, thus effectively overcoming paclitaxel resistance in breast cancer. This study provides valuable insights into the potential clinical applications of GLE in reversing multidrug resistance, offering hope for improved breast cancer treatment strategies. •Ganoderma lucidum extract (GLE) markedly increased the toxicity of paclitaxel in 3D MCF-7 cells to reverse drug resistance.•GLE effectively inhibited P-gp efflux function by decreasing ATPase activity rather than P-gp protein expression.•GLE inhibited the phosphorylation of ERK1/2, suggesting that the reversal effect of GLE is associated with MAPK pathway.