Quinazoline derivative compound (11d) as a novel angiogenesis inhibitor inhibiting VEGFR2 and blocking VEGFR2-mediated Akt/mTOR /p70s6k signaling pathway

Document Type: Original Article

Authors

1 Department of Pharmacy, Anhui Medical University, Hefei 230032, China

2 Department of Pharmacy, Xiangnan University, Chenzhou 423000, China

3 Department of Chirurgery, First Affiliated Hospital of Anhui Medical University, Hefei 230032, China

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.

Keywords


1. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell 2011; 146: 873-887.

2. Qin Bromberg L, White JL, Qian CN. Opportunities and challenges in tumor angiogenesis research; back and forth between benchand bed.Adv Cancer Res 2012; 113: 191-239.

3. Gasparini G, Longo R, Toi M, et al. Angiogenic inhibitors: a new therapeutic strategy in oncology. Nat Clin Pract Oncol 2005; 2:  562-577.

4. Bishayee A, Darvesh AS. Angiogenesis in hepato-cellular carcinoma: a potential target for chemo-prevention and therapy. Curr Cancer Drug Targets 2012; 12: 1095-1118.

5. Kerbel RS. Tumor angiogenesis. N Engl J Med 2008; 358: 2039-2049.

6. Shibuya M. Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies. Genes Cancer 2011; 2: 1097-1105.

7. Spangenberg HC, Thimme R, Blum HE. Targeted therapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2009; 6: 423-432.

8. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9: 669-676.

9. Koch S, Tugues S, Li X, et al. Signal transduction by vascular endothelial growth factor receptors. Biochem J 2011; 437: 169-183.

10. Takahashi S. Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. Biol Pharm Bull  2011; 34:  1785-1788.

11. Kankanala J, Latham AM, Johnson AP, et al. A combinatorial in silico and cellular approach to identify a new class of compounds that target VEGFR2 receptor tyrosine kinase activity and angiogenesis. Br J Pharmacol 2012; 166: 737-748.

12. Wysocki PJ. Targeted therapy of hepatocellular cancer. Expert Opin Investig Drugs  2010; 19: 265-274.

13. Llovet JM, Ricci S, Mazzaferro V. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med   2008; 359: 378-390.

14. Kim R, Byrne MT, Tan A, et al. What is the indication for sorafenib in hepatocellular carcinoma? A clinical challenge. Oncology 2011; 25: 283-291.

15. Yu GJ,  Li Z, Tang L, et al. Synthesis and evaluation of 2,4-disubstituted quinazoline derivatives with potent anti-angiogenesis activities. Molecules 2014; 19: 8916-8932.

16. Saraswati S, Kumar S, Alhaider AA. α-santalol inhibits the angiogenesis and growth of human prostate tumor growth by targeting vascular endothelial growth factor receptor 2-mediated AKT/mTOR/P70S6K signaling pathway. Mol Cancer 2013; 12: 147.

17. Reuben SC, Gopalan A, Petit DM, et al. Modulation of angiogenesis by dietary phytoconstituents in the prevention and intervention of breast cancer. Mol Nutr Food Res 2012; 56: 14-29.

18. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005; 438: 967-974.

19. Morabito A, De Maio E, Di Maio M, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions. Oncologist 2006; 11: 753-764.

20. Shaw RJ and Cantley Ras LC. PI(3)K and mTOR signalling controls tumour cell growth. Nature  2006; 441: 424-430.

21. Seeliger H, Guba M, Kleespies A, et al.  Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis. Cancer Metastasis Rev 2007; 26: 611-621.

22. Radisavljevic Z. AKT as locus of cancer angiogenic robustness and fragility. J Cell Physiol  2013; 228: 21-24. 

23. Pang X, Yi Z, Zhang X, et al. Acetyl-11-keto-beta-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. Cancer Res 2009; 69: 5893-5900.

24. Li W, Tan D, Zhang Z, et al. Activation of Akt-mTOR-p70S6K pathway in angiogenesis in hepatocellular carcinoma. Oncol Rep  2008; 204: 713-719.

25. Ciuffreda L, Di Sanza C, Incani, UC, et al. The mTOR pathway: a new target in cancer therapy. Curr Cancer Drug Targets 2010; 10: 484-49.

26. Bian CX, Shi Z, Meng Q. P70S6K 1 regulation of angiogenesis through VEGF and HIF-1alpha expression. Biochem Biophys Res Commun  2010; 398: 395-399.