L-A03, a dihydroartemisinin derivative, promotes apoptotic cell death of human breast cancer MCF-7 cells by targeting c-Jun N-terminal kinase

L-A03 is a dihydroartemisinin derivative and exerts distinct anti-tumor activity in vitro. Previous studies showed that induction of autophagy and deficiency in nitric oxide (NO) generation contributed to apoptotic cell death in L-A03-treated MCF-7 cells. However, the detailed mechanism is still unclear. In this study, the role of mitogen-activated protein kinases (MAPKs) in this apoptotic process was investigated. L-A03 (7.5-30 mu M) selectively inhibited the activation of c-Jun N-terminal protein kinase (JNK) with no significant effect on extracellular signal related kinase (ERK) and p38. In addition, the possible mechanism of interaction between JNK and L-A03 was also investigated by molecular docking. In the presence of SP600125, a specific JNK inhibitor, induction of autophagy and apoptosis with L-A03 at 15 mu M were elevated, but NO generation was attenuated, indicating that JNK inactivation is essential for apoptotic cell death. Interestingly, autophagy induction and NO generation did not affect the activation of JNK, demonstrating that JNK is upstream to autophagy and NO. Taken together, L-A03-induced JNK inactivation enhances autophagic and apoptotic cell death, but represses the generation of NO. This study provides a new insight on the mechanism of L-A03-induced cell death by targeting JNK.