Abstract
Pancreatic cancer is a common malignant tumor with high mortality, and novel therapeutic options have focused on ameliorating its poor prognosis. TEOA, a traditional Chinese herbal medicine, exhibits anti-inflammatory and anti-cancer activities. Our recent study has shown that TEOA inhibits proliferation and induces DNA damage in diffuse large B-cell lymphoma cells by activating the ROS-mediated p38 MAPK pathway. However, its effects on pancreatic cancer cells remain unknown. In the present study, we evaluated the effects of TEOA on the proliferation, migration of pancreatic cancer cells and explored the possible underlying mechanism of action. We found that TEOA significantly inhibited the proliferation and migration of pancreatic cancer cells in a time- and dose-dependent manner. Mechanistically, TEOA significantly induced mitochondrial dysfunction in PANC1 and SW1990 cells, as evidenced by the collapse of the mitochondrial membrane potential, exhausted ATP level, and excessive accumulation of intracellular ROS. Notably, our further experiments showed that TEOA induced autophagic cell death in pancreatic ductal adenocarcinoma cells by inactivating the ROS-dependent mTOR/p70S6k signaling pathway. More importantly, both pharmacological or genetic blocking of the autophagic flux signal could partly restore the cytotoxicity of TEOA, whereas activation of autophagy by rapamycin or EBSS induced starvation facilitated the cytotoxicity of TEOA. Concomitantly, N-acetylcysteine, a ROS scavenger, abolished the inhibition of the mTOR signaling pathway, thus preventing autophagy and restoring cell viability. Taken together, our results reveal that TEOA can lead to ROS-dependent autophagic cell death of pancreatic cancer cells by inducing mitochondrial dysfunction, which might be a promising therapeutic agent for pancreatic cancer.
Highlights
Pancreatic cancer is an aggressive malignancy with poor prognosis and limited treatment options and is the seventh leading cause of cancer mortality worldwide (Allemani et al, 2018)
We found that co-treatment with the ROS scavenger NAC could not restore the membrane potential (MMP), which confirmed the upstream position of mitochondrial dysfunction (Supplementary Figure 4)
DHA inhibits the proliferation of leukemia cells by inducing ferroptosis (Du et al, 2019)
Summary
Pancreatic cancer is an aggressive malignancy with poor prognosis and limited treatment options and is the seventh leading cause of cancer mortality worldwide (Allemani et al, 2018). Owing to the high malignancy and poor prognosis of pancreatic cancer, it is imperative to develop more effective and less toxic therapeutic strategies. Traditional medicinal herbs have long been used in China because of their low toxicity and high activity. Natural compounds derived from medicinal herbs have been demonstrated to be the mainstay of anticancer drug screening. Many FDA-approved anti-cancer drugs have been developed from natural compounds, such as paclitaxel, camptothecin, and podophyllotoxin (Cragg et al, 2009; Newman and Cragg, 2012). Our previous studies demonstrated that dihydroartemisinin, derived from the Chinese plant Artemisia annua, preferentially targeted acute myeloid leukemia cells by inducing ferroptotic cell death while exhibiting low toxicity on normal hematopoietic progenitor cells (Du et al, 2019). Gambogic acid, derived from the Chinese herb Garcinia hanburyi, induces T-cell acute lymphoblastic leukemia cell apoptosis by downregulating the β-catenin signaling pathway (Wang et al, 2020)
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