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 mouse in vivo.
Conclusion
Indox inhibited the proliferative, invasive, and metastatic potentials of PDAC in vitro and in vivo. Therefore, Indox could a therapeutic candidate for treating spontaneously occurring PDAC via blocking the RAF/ERK, AKT and SAPK/JNK pathways.
Methods
Randomized 3-month-old LSL-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 in KPCflox-derived PDAC cells in vitro.
Results
Prolonged survival by Indox via intraperitoneal administration was observed in the KPCflox mice. Indox inhibited tumor proliferation accompanied with low levels of nuclear phosphorylated cyclin-dependent kinase (p-CDK) and cyclin B1 in vivo. Furthermore, Indox inhibited the migration/invasive activities of PDAC via down-regulation of matrix metalloproteinase (MMP)-9 in vitro and in 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.