Discruption of akt/hif1 signaling can enhance the therapeutic efficacy of ischemic hypoxia and chemotherapy

Abstract

PURPOSE: This study investigates the possible molecular basis leading to failure in a treatment that is composed of hypoxia and chemotherapy in a rat orthotopic hepatoma model. EXPERIMENTAL DESIGNS: Cell viability after cisplatin treatments under normoxia and hypoxia would be measured by 3,[4,5-dimethylthiazol-2-yl] -2,5-diphenyl-tetrazolium bromide (MTT) assay and cytofluorometric annexin-V apoptotic assay would be used to compare the apoptotic cells induced by cisplatin under normoxia and hypoxia. Western blotting would be employed to determine the akt/hif1 signaling. In vivo hypoxic condition was induced by hepatic artery ligation, whereas chemotherapeutic effect was achieved by intraportal injection of cisplatin. Hif1 inhibitor was administered to blockade Hif-1α expression both in vitro and in vivo. RESULTS: Cell viability was higher under hypoxic than normoxic conditions shown by MTT assay and decreased apoptotic cells could be observed by apoptotic assay under hypoxia. Hif-1α and akt were regulated each other under hypoxic conditions to confer cisplatin resistance in vitro. In an rat orthotopic hepatoma model, combining blockade of Hif-1α activity with ischemic hypoxia significantly enhanced the efficacy of chemotherapy, leading to suppression of tumor growth and prolongation of animal survival. CONCLUSION: Combined Hif1 inhibitor with hypoxia and chemotherapy can be a new and promising therapeutic approach to the treatment of HCC.