Abstract:

Objective(s): We previously reported a series of quinazoline derivatives as vascular-targeting anticancer agents. In this study, we investigated the mechanism underlying the anti-angiogenic activity of the quinazoline derivative compound 11d. Materials and Methods: We examined the effects of quinazoline derivative 11d on vascular endothelial growth factor receptor-2 (VEGFR2) activation via VEGFR2-specific activation assay. Reverse transcription and immunohistochemistry were used to detect vascular endothelial growth factor (VEGF), VEGFR2, and the VEGFR2-mediated Akt/mTOR/p70s6k signaling pathway in human umbilical vascular endothelial cells and hepatocellular carcinoma cells (HepG-2) after treatment with various concentrations of 11d (0, 6.25, 12.5, and 25 μM) for 24 hr. Results: The compound 11d exhibited potent inhibitory activity against VEGFR2 with an IC50 of 5.49 μM. This compound significantly downregulated VEGF, VEGFR2, and the VEGFR2-mediated Akt/mTOR/p70s6k signaling pathway in vitro. Conclusion:The mechanism underlying the anti-angiogenic activity of the quinazoline derivative 11d possibly involves the inhibition of VEGFR2 and the downregulation of VEGF, VEGFR2, and the VEGFR2-mediated Akt/mTOR/p70s6k signaling pathway. Overall, the findings indicate that the studied class of compounds is a source of potential antiproliferative and anti-angiogenic agents, which must be further investigated.

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