Abstract
Background
Penfluridol (PF) is an FDA approved antipsychotic drug, which shows anticancer activity recently. However, the anticancer effects and underlying mechanisms of PF on gallbladder cancers (GBCs) is not well-established.
Methods
Herein, cytotoxicity, cell proliferation, cell apoptosis, and cell metastasis assays were used to investigate the anticancer activity of PF on GBCs. Glucose consumption and lactic production assays were used to detect the glycolysis alteration. Western blotting was used to detect the corresponding signaling change after PF treatment. Nude mice were utilized to study the anticancer activity of PF in vivo.
Results
Here, we first observed that PF significantly suppress GBC cells proliferation and metastasis. After PF treatment, the glucose consumption and lactic production of GBCs were significantly increased. In addition, we found that inhibition of glycolysis enhanced the anticancer activity of PF. Further studies demonstrated that glycolysis was medicated by the activation of AMPK/PFKFB3 signaling pathway. Mechanistically, we demonstrated that AMPK/PFKFB3 signaling pathway mediated glycolysis was a resistant mechanism of PF in GBCs.
Conclusions
Inhibition of AMPK enhanced the anticancer effects of PF on GBCs. therefore, our studies provided a novel insight into repurposing PF as anticancer agent for GBCs, and AMPK inhibition in combination with PF could be a potential therapeutic approach for GBCs.