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Anti-tumor activity of cediranib, a pan-vascular endothelial growth factor receptor inhibitor, in pancreatic ductal adenocarcinoma cells

  • Majid MomenyEmail author
  • Zivar Alishahi
  • Haniyeh Eyvani
  • Fatemeh Esmaeili
  • Azam Zaghal
  • Parisa Ghaffari
  • Javad Tavakkoly-Bazzaz
  • Kamran Alimoghaddam
  • Ardeshir Ghavamzadeh
  • Seyed H. GhaffariEmail author
Original paper
  • 95 Downloads

Abstract

Purpose

Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal subtype of pancreatic cancer, with a 5-year survival rate of < 3%. Early tumor dissemination, late diagnosis and insensitivity to conventional treatment are the major reasons for its high mortality rate. Members of the vascular endothelial growth factor (VEGF) family are overexpressed in PDAC and play important roles in its malignant progression, suggesting that VEGF-targeted therapies may interrupt the proliferation and motility of PDAC cells. Here, we evaluated the anti-tumor activity of cediranib, a pan-VEGF receptor inhibitor, on PDAC cells.

Methods

Anti-proliferative effects of cediranib were determined using cell proliferation and crystal violet staining assays. Annexin V/PI staining, radiation therapy, and cell migration and invasion assays were carried out to examine the effects of cediranib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of cediranib.

Results

We found that cediranib decreased PDAC 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 the sensitivity of PDAC cells to chemotherapeutic agents such as gemcitabine and paclitaxel, and potentiated the effects of radiation therapy on PDAC cell growth inhibition and apoptosis induction. Furthermore, we found that treatment with cediranib impaired PDAC cell migration and invasion via expression reduction of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, N-cadherin and Snail.

Conclusions

Our data indicate that cediranib may exhibit anti-tumor activity in PDAC cells and provide a rationale for further investigation of the potential of VEGF receptor-targeted therapies for the treatment of PDAC.

Keywords

Pancreatic ductal adenocarcinoma VEGF family Cediranib Therapeutic sensitization 

Notes

Acknowledgements

This study was financially supported by a grant from the Hematology/Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Author’s contributions

M.M. designed the research; Z.A., H.Y. A.Z. and P.G. conducted the research; M.M., J.T., K.A. and A.G. analyzed the data; M.M. and Z.A. wrote the paper; M.M. and S.H.G. were primarily responsible for the final content. All authors have reviewed and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

There is no conflict of interest.

Supplementary material

13402_2019_473_MOESM1_ESM.docx (333 kb)
ESM 1 (DOCX 333 kb)

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Copyright information

© International Society for Cellular Oncology 2019

Authors and Affiliations

  1. 1.Turku Bioscience CenterUniversity of Turku and Åbo Akademi UniversityTurkuFinland
  2. 2.Hematology/Oncology and Stem Cell Transplantation Research CenterTehran University of Medical SciencesTehranIran
  3. 3.Department of Medical Genetics, School of MedicineTehran University of Medical SciencesTehranIran

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