Indirubin 3′-Oxime Inhibits Migration, Invasion, and Metastasis In Vivo in Mice Bearing Spontaneously Occurring Pancreatic Cancer via Blocking the RAF/ERK, AKT, and SAPK/JNK Pathways

摘要

BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high invasive and metastatic potential. We generated a spontaneous PDAC mouse model and examined the therapeutic potential of indirubin 3′-oxime (Indox) against PDAC bearing mousein vivo.METHODS:Randomized 3-month-oldLSL-KrasG12D/+;Trp53flox/+;Pdx-1-cre(KPCflox) mice were intraperitoneally injected with 40 mg/kg Indox (n?= 9) or a vehicle (n?= 10) twice a week. At the end point, tumor status including proliferation, direct invasion, and distant metastasis was analyzed histopathologically. The inhibitory potentials of Indox for proliferation, migration/invasion, and the phosphorylation of target molecules were determined inKPCflox-derived PDAC cellsin vitro.RESULTS:Prolonged survival by Indox via intraperitoneal administration was observed in theKPCfloxmice. Indox inhibited tumor proliferation accompanied with low levels of nuclear phosphorylated cyclin-dependent kinase (p-CDK) and cyclin B1in vivo. Furthermore, Indox inhibited the migration/invasive activities of PDAC via down-regulation of matrix metalloproteinase (MMP)-9in vitroandin vivo. Antibody array and immunoblotting analysis revealed that Indox inhibited the phosphorylation of multiple molecules, including key upstream proteins of MMP-9 in RAF/extracellular signal-regulated kinase (ERK), AKT, and stress-activated protein kinase/c-Jun-N-terminal kinase (SAPK/JNK) pathways.CONCLUSION:Indox inhibited the proliferative, invasive, and metastatic potentials of PDACin vitroandin vivo. Therefore, Indox could a therapeutic candidate for treating spontaneously occurring PDAC via blocking the RAF/ERK, AKT and SAPK/JNK pathways.