Arsenic trioxide plus PX-478 achieves effective treatment in pancreatic ductal adenocarcinoma

• ATO plus PX-478 (HIF-1 inhibitor) controls PDAC by ROS accumulation.
• HIF-1 directly activates the transcription of FOXO1 in PDAC.
• HIF-1 removes intracellular ROS by the FOXO1/SESN3 pathway.

Arsenic trioxide (ATO) has been selected as a promising treatment not only in leukemia but also in solid tumors. Previous studies showed that the cytotoxicity of ATO mainly depends on the induction of reactive oxygen species. However, ATO has only achieved a modest effect in pancreatic ductal adenocarcinoma, suggesting that the existing radical scavenging proteins, such as hypoxia inducible factor-1, attenuate the effect. The goal of this study is to investigate the effect of combination treatment of ATO plus PX-478 (hypoxia-inducible factor-1 inhibitor) and its underlying mechanism. Here, we showed that PX-478 robustly strengthened the anti-growth and pro-apoptosis effect of ATO on Panc-1 and BxPC-3 pancreatic cancer cells in vitro. Meanwhile, in vivo mouse xenograft models also showed the synergistic effect of ATO plus PX-478 compared with any single agent. Further studies showed that the anti-tumor effect of ATO plus PX-478 was derived from the reactive oxygen species-induced apoptosis. We next confirmed that Hypoxia-inducible factor-1 cleared reactive oxygen species by its downstream target, forkhead box O transcription factors, and this effect may justify the strategy of ATO plus PX-478 in the treatment of pancreatic cancer.