Enhancing responsiveness of pancreatic cancer cells to gemcitabine treatment under hypoxia by heme oxygenase-1 inhibition

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies and has one of the worst prognoses leading to a meager 5-year survival rate of ∼8%. Chemotherapy has had limited success in extending the life span of patients with advanced PDAC due to poor tumor perfusion and hypoxia-induced resistance. Hypoxia reprograms the gene expression profile and upregulates the expression of multiple genes including heme oxygenase-1 (HO-1), which provide survival advantage to PDAC cells. However, the relationships between HO-1, hypoxia, and response to chemotherapy is unclear. Our results showed that hypoxia upregulates the expression of HO-1 in PDAC cells, and HO-1 inhibition using the HO-1 inhibitors zinc protoporphyrin, tin protoporphyrin IX (SnPP), and HO-1 knockout using CRISPR/Cas9 suppresses the proliferation of PDAC cells under hypoxia and sensitize them to gemcitabine under in vitro conditions. Treating orthotopic tumors with SnPP, or SnPP in combination with gemcitabine, significantly reduced the weight of pancreatic tumors ( P P