Vandetanib-eluting radiopaque beads for chemoembolization: physicochemical evaluation and biological activity of vandetanib in hypoxia
| Autor: | Alice E. Hagan, Gary Phillips, Andrew L. Lewis, Adam Westhorpe, Andrew W. Lloyd, Sami A. Znati, Ricky A. Sharma, Rebecca Carter, Wendy M. Macfarlane |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Programmed cell death Carcinoma Hepatocellular MAP Kinase Signaling System Context (language use) Apoptosis Vandetanib Downregulation and upregulation Piperidines Cell Line Tumor medicine Human Umbilical Vein Endothelial Cells Humans Pharmacology (medical) Epidermal growth factor receptor Chemoembolization Therapeutic Hypoxia Pharmacology biology Neovascularization Pathologic Chemistry Vascular Endothelial Growth Factors Cell Cycle Liver Neoplasms Cell cycle Drug Liberation Oncology Cell culture Cancer research biology.protein Quinazolines medicine.drug |
| Zdroj: | Anti-cancer drugs. 32(9) |
| ISSN: | 1473-5741 |
| Popis: | Vandetanib-eluting radiopaque beads (VERB) have been developed for use in transarterial chemoembolization of liver tumours, with the goal of combining embolization with local delivery of antiangiogenic therapy. The objective of this study was to investigate how embolization-induced hypoxia may affect antitumoural activity of vandetanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), in the context of hepatocellular carcinoma (HCC) treatment. We studied the effect of vandetanib on proliferation, cell cycle and apoptosis of HCC cells, in hypoxic conditions, as well as the direct effects of the beads on 3D HCC spheroids. Vandetanib suppressed proliferation and induced apoptosis of HCC cells in vitro and was equipotent in hypoxic and normoxic conditions. High degrees of apoptosis were observed among cell lines in which vandetanib suppressed ERK1/2 phosphorylation and upregulated the proapoptotic protein Bim, but this did not appear essential for vandetanib-induced cell death in all cell lines. Vandetanib also suppressed the hypoxia-induced secretion of VEGF from HCC cells and inhibited proliferation of endothelial cells. Incubation of tumour spheroids with VERB led to sustained growth inhibition equivalent to the effect of free drug. We conclude that vandetanib has both antiangiogenic and direct anticancer activity against HCC cells even in hypoxic conditions, warranting the further evaluation of VERB as novel anticancer agents. |
| Databáze: | OpenAIRE |
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