M. canadensis and its active component salvianolic acid B overcome paclitaxel resistance in gastric cancer via ROS–ER stress signaling

Paclitaxel (PTX) is widely used for gastric cancer treatment; however, PTX resistance (PTXR) significantly limits clinical efficacy. To investigate the potential of Mentha canadensis and its bioactive component, salvianolic acid B, to overcome PTX resistance in gastric cancer. The cytotoxic effects of M. canadensis and salvianolic acid B, either alone or in combination with PTX, were assessed by cell viability assays. Total RNA sequencing was conducted on M. canadensis–treated PTXR cells to identify differentially expressed genes and enriched pathways. Expression levels of NOXA, PERK, ATF4, and other apoptotic markers were assessed using western blotting. Reactive oxygen species (ROS) production and mitochondrial membrane potential changes were evaluated using flow cytometry. siRNA-mediated knockdown of NOXA and ATF4 was performed to determine roles in apoptosis. The combination of M. canadensis and PTX overcame PTX resistance. M. canadensis treatment significantly increased ROS production, apoptosis, and endoplasmic reticulum stress–related pathways in PTXR cells. M. canadensis induced apoptosis by upregulating NOXA. ROS accumulation further contributed to M. canadensis–induced apoptosis. Salvianolic acid B, a major bioactive compound of M. canadensis, enhanced PTX-induced apoptosis by upregulating ATF4 and NOXA and causing ROS accumulation. Salvianolic acid B acted synergistically with PTX by decreasing cell viability and promoting caspase-dependent apoptosis. M. canadensis and its active component salvianolic acid B sensitize PTXR gastric cancer cells to apoptosis by inducing ROS accumulation and ER stress–mediated NOXA upregulation. Overall, M. canadensis is a potential therapeutic agent for overcoming PTX resistance in gastric cancer.