Chloroxine inhibits pancreatic cancer progression through targeted antagonization of the PI3K/AKT/mTOR signaling pathway.

Abstract

Patients with pancreatic cancer have a dismalprognosis due to tumor cell infiltration andmetastasis. Many reportshave documentedthat EMT and PI3K-AKT-mTOR axis control pancreatic cancer cell infiltrationand metastasis. Chloroxine is an artificially synthesized antibacterial compound that demonstrated anti-pancreatic cancer effects in our previous drug-screening trial. We have explored the impact of chloroxine on pancreatic cancergrowth, infiltration, migration, and apoptosis. The proliferation of pancreatic cancer cell lines (PCCs) treated with chloroxine was assessed through real-time cell analysis (RTCA), colony formation assay, CCK-8 assay, as well as immunofluorescence. Chloroxine effectson the infiltrative and migratory capacities of PCCs were assessed via Transwell invasion and scratch experiments. To assess the contents of EMT- and apoptosis-associatedproteins in tumor cells, we adopted Western immunoblotting as well as immunofluorescence assays, and flow cytometry to determinechloroxine effectson PCCs apoptosis. The in vivo chloroxineantineoplastic effectswere exploredin nude mice xenografts. Chloroxine repressed pancreatic cancer cellgrowth, migration, and infiltration in vitro, as well asin vivo, and stimulated apoptosis of thePCCs. Chloroxine appeared to inhibit PCC growth byKi67 downregulation; this targeted and inhibited aberrant stimulation of the PI3K-AKT-mTOR signaling cascade, triggered apoptosis in PCC via mitochondria-dependent apoptosis, and modulated the EMT to inhibit PCC infiltration and migration. Chloroxine targeted and inhibited the PI3K-AKT-mTOR cascade to repress PCCs growth, migration, as well as invasion, and triggered cellular apoptosis. Therefore, chloroxine may constitute a potential antineoplastic drug for the treatment of pancreatic cancer.