Analysis of Antiproliferative and Chemosensitizing Effects of Sunitinib on Human Esophagogastric Cancer Cells: Synergistic Interaction With Vandetanib via Inhibition of Multireceptor Tyrosine Kinase Pathways

6533b827fe1ef96bd1287265

RESEARCH PRODUCT

Analysis of Antiproliferative and Chemosensitizing Effects of Sunitinib on Human Esophagogastric Cancer Cells: Synergistic Interaction With Vandetanib via Inhibition of Multireceptor Tyrosine Kinase Pathways

Florian Heidel Ines Gockel Carl C. Schimanski Annett Mueller Peter R. Galle Hauke Lang Markus Moehler Orestis Lyros

subject

Cancer Research Umbilical Veins Indoles Esophageal Neoplasms Apoptosis Vandetanib Tyrosine-kinase inhibitor Receptor tyrosine kinase chemistry.chemical_compound Piperidines Sunitinib Medicine Drug Interactions Epidermal growth factor receptor Phosphorylation Cells Cultured biology Sunitinib Reverse Transcriptase Polymerase Chain Reaction Drug Synergism Flow Cytometry ErbB Receptors Oncology Phosphorylation Drug Therapy Combination medicine.drug Signal Transduction medicine.medical_specialty medicine.drug_class Blotting Western Antineoplastic Agents Stomach Neoplasms Internal medicine Humans Pyrroles Propidium iodide RNA Messenger Protein Kinase Inhibitors Cell Proliferation Vascular Endothelial Growth Factor Receptor-1 business.industry Cancer medicine.disease Vascular Endothelial Growth Factor Receptor-3 Vascular Endothelial Growth Factor Receptor-2 Endocrinology chemistry Cancer research biology.protein Quinazolines Endothelium Vascular business Proto-Oncogene Proteins c-akt

description

The receptor tyrosine kinases (RTKs), epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 1-3 (VEGFR1-3), are frequently expressed in gastric cancer and are putative therapeutic targets in this disease. We have investigated the anti-proliferative and chemosensitizing properties of the multitargeted small-molecule RTK inhibitors sunitinib and vandetanib in a panel of 4 human gastric and esophageal cancer cell lines. In the 1st instance, the expression of potential targets of these small-molecule inhibitors was examined by reverse transcriptase-polymerase chain reaction, western blotting, and flow cytometry. EGFR mRNA and protein was detected in all cases, with VEGFR2 expression noted in all but 1 line. Both EGF and VEGF were shown to stimulate tumor cell growth, and both sunitinib and vandetanib were found to be associated with significant dose-dependent inhibition of proliferation and an enhancement of apoptosis, as determined by MTT and propidium iodide/Annexin V labeling assays, respectively. The addition of sunitinib to VEGF-stimulated NCI-N87 cells was associated with a reduction in MAPK phosphorylation (pMAPK) but not Akt phosphorylation (pAkt), whereas the addition of vandetanib was associated with reductions in both VEGF- and EGF-mediated VEGFR2 phosphorylation, pMAPK and pAkt. Co-administration of sunitinib significantly enhanced the sensitivity of MKN-45 cells to cisplatin and irinotecan. In addition, vandetanib synergistically enhanced the sunitinib-associated inhibition of gastric cancer cell growth. In conclusion, these preliminary data confirm the importance of EGFR and VEGFR signaling in gastric cancer and suggest that the simultaneous inhibition of RTK-pathways through sunitinib and vandetanib may provide therapeutic benefit in this disease.

year	journal	country	edition	language
2009-12-28

https://publons.com/wos-op/publon/31118369/