Cediranib, a pan-inhibitor of vascular endothelial growth factor receptors, inhibits proliferation and enhances therapeutic sensitivity in glioblastoma cells.

Abstract

AIMS:

Glioblastoma (GB) is the most aggressive type of brain tumor. Rapid progression, active angiogenesis, and therapy resistance are major reasons for its high mortality. Elevated expression of members of the vascular endothelial growth factor (VEGF) family suggests that anti-VEGF therapies may be potent anti-glioma therapeutic approaches. Here, we evaluated the anti-tumor activity of cediranib, a pan inhibitor of the VEGF receptors, on GB cells.

MATERIALS AND METHODS:

Anti-proliferative effects of cediranib were determined using MTT, crystal-violet staining, clonogenic and anoikis resistance assays. Apoptosis induction was assessed by Annexin V/PI staining and Western blot analysis and aggressive abilities of GB cells were investigated using cell migration/invasion assays and zymography. Small-interfering RNA (siRNA)-mediated Knockdown was used to study resistance mechanisms. The anti-proliferative and apoptotic effects of cediranib in combination with radiotherapy, temozolomide, bevacizumab were also evaluated using MTT, Annexin V/PI staining and Western blot analysis for cleaved PARP-1.

KEY FINDINGS:

Cediranib reduced GB cell proliferation, induced apoptotic cell death and inhibited the aggressive abilities of GB cells. Cediranib synergistically increased the anti-proliferative and apoptotic effects of radiotherapy and bevacizumab and augmented the sensitivity of GB cells to temozolomide chemotherapy. In addition, knockdown of MET and AKT potentiated cediranib sensitivity in cediranib-resistant GB cells.

SIGNIFICANCE:

These findings suggest that cediranib, alone or in combination with other therapeutics, is a promising strategy for the treatment of GB and provide a rationale for further investigation of the therapeutic potential of cediranib for the treatment of this fatal malignancy.

• Authors: Majid Momeny, Sahar Shamsaiegahkani, Bahareh Kashani, Sepideh Hamzehlou, Fatemeh Esmaeili, Hassan Yousefi, Shiva Irani, Seyed A Mousavi, Seyed H Ghaffari
• Journal: Life sciences (Life Sci) Vol. 287 Pg. 120100 (Dec 15 2021) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 34715143 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Growth Inhibitors
• Protein Kinase Inhibitors
• Quinazolines
• Receptors, Vascular Endothelial Growth Factor
• cediranib

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation (drug effects, physiology)
• Glioblastoma (drug therapy, metabolism, pathology)
• Growth Inhibitors (pharmacology, therapeutic use)
• Humans
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Quinazolines (pharmacology, therapeutic use)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors, metabolism)