Dihydrotanshinone I potentiates the anti-tumor activity of cisplatin by activating ROS-mediated ER stress through targeting HSPD1 in lung cancer cells

Lung cancer represents one of the most lethal malignancies, characterized by the highest incidence and mortality rates globally. Cisplatin-based chemotherapy exerts powerful anti-tumor activities in lung cancer, whereas its clinical application was limited due to the severe side effects. Dihydrotanshinone I (DHTS), a root extract from Salvia miltiorrhiza, exhibits diverse biological functions, encompassing liver protection, anti-inflammatory properties, promotion of osteoclast differentiation, and induction of apoptosis in tumor cells. DHTS exerts anti-tumor effects in various cancers, however, its biological functions in lung cancer are largely unknown. We demonstrated that DHTS synergistically increased the tumor suppressive effects of cisplatin in lung cancer cells by activating reactive oxygen species (ROS)-mediated endoplasmic reticulum stress (ER stress) and c-Jun Nterminal kinase (JNK) signaling pathways, both in vitro and in vivo. Additionally, DHTS induced excessive ROS accumulation by inhibiting the expression of Heat Shock Proteins 60 (HSPD1). Silencing HSPD1 augmented the anti-tumor effects of DHTS in lung cancer cells, primarily through the stimulation of ROS-mediated ER stress and JNK pathways. Our study suggests that DHTS possesses druggable potential, and combined therapy with DHTS and cisplatin may be a promising therapeutic strategy for certain lung cancer patients.