Isolinderalactone sensitizes oxaliplatin-resistance colorectal cancer cells through JNK/p38 MAPK signaling pathways

Isolinderalactone (ILL), a sesquiterpene lactone compound, can be extracted from the root of Lindera aggregate. Physiological activities of ILL, including anti-inflammatory and anti-proliferative effects, have been investigated in multiple diseases. Nevertheless, little is known regarding its anti-cancer activities and the mechanism of action of ILL in targeting human CRC cells.To determine ILL-mediated anti-proliferative effects on oxaliplatin (Ox)-sensitive and resistant colorectal cancer (CRC) cells and underlying mechanisms involved in its effects focusing on signal transduction.Inhibitory effect of ILL on CRC cells was evaluated by analyzing mitochondrial membrane potential (MMP) dysfunction and multi-caspase activity. Apoptosis-regulating proteins and JNK/p38 signaling molecules were monitored by Western blotting. ROS-dependent physiological modifications by ILL were confirmed by pretreatment with N-acetylcysteine (NAC). Moreover, the involvement of JNK/p38 signaling in ROS-mediated apoptosis was verified by treatment with SP600125 (JNK inhibitor) and SB203580 (p38 inhibitor).ILL decreased cell viability and colony formation in both CRC Ox-sensitive (HCT116 and HT29) and Ox-resistant (OxR) (HCT116-OxR and HT29-OxR) cells. ILL induced G2/M phase cell cycle arrest, ROS generation, phosphorylated (p)JNK/p38 MAPK activation, mitochondrial membrane potential (MMP) depolarization, and multi-caspase activation, which eventually triggered apoptotic cell death of CRC cells. In addition, combined treatment with ILL and SP600125, SB203580, or pan-caspase inhibitor (Z-VAD-FMK) prevented decreases in cell viability seen after treatment with ILL alone. Pretreatment with NAC attenuated ILL-mediated apoptosis, ROS production, and p-JNK/p38 expression.Taken together, our results suggest that ILL can exert its anticancer effect in CRC Ox-sensitive and OxR cells by inducing ROS-mediated apoptosis through JNK/p38 MAPK signaling pathways. This is the first study demonstrating that ILL has a potential to improve drug efficacy against resistance mechanisms, providing a new insight into therapeutic strategies targeting drug-resistant CRC.