Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal subtype of pancreatic cancer, with a 5-year survival rate of less than 3%. Early tumor dissemination, late diagnosis, and insensitivity to conventional treatments are the major reasons for its high mortality rate. Members of vascular endothelial growth factor (VEGF) family are overexpressed in PDAC and play important roles in its malignant progression, suggesting that VEGF-targeted therapies are potentially promising to interrupt proliferation and motility of PDAC cells. Here, we evaluated the anti-tumor activity of cediranib, a pan-VEGF receptor inhibitor, on PDAC cells.
Anti-proliferative effects of cediranib were determined using cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and cell migration and invasion assays were carried out to examine the effects of cediranib on apoptosis, radiosensitivity, and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analysis were applied to elucidate the molecular mechanisms for the anti-tumor activity of cediranib.
Cediranib hindered cell proliferation and clonogenic survival and induced apoptotic cell death through inhibition of the anti-apoptotic proteins cIAP1, XIAP, MCL-1, and survivin. Combination with cediranib synergistically increased sensitivity to the chemotherapeutic agents gemcitabine and paclitaxel and potentiated the effects of radiation therapy on inhibition of cell growth and induction of apoptosis. Furthermore, treatment with cediranib impaired PDAC cell migration and invasion via reduction of epithelial-to-mesenchymal transition (EMT) markers ZEB1, N-cadherin and Snail.
These findings suggest that cediranib has potential anti-tumor activity in the PDAC cells and provide a rationale for further investigation on the therapeutic potential of this VEGFR-targeted therapy in the treatment of PDAC.
Clinical trial identification
Legal entity responsible for the study
Hematology/Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
All authors have declared no conflicts of interest.