Exploring quercetin and luteolin derivatives as antiangiogenic agents

Lists

Tools

Ravishankar, D., Watson, K. A. ORCID: https://orcid.org/0000-0002-9987-8539, Boateng, S. Y., Green, R. J., Greco, F. and Osborn, H. M.I. ORCID: https://orcid.org/0000-0002-0683-0457 (2015) Exploring quercetin and luteolin derivatives as antiangiogenic agents. European Journal of Medicinal Chemistry, 97. pp. 259-274. ISSN 0223-5234

Preview

Text - Accepted Version
· Please see our End User Agreement before downloading.
2MB

It is advisable to refer to the publisher's version if you intend to cite from this work. See Guidance on citing.

To link to this item DOI: 10.1016/j.ejmech.2015.04.056

Abstract/Summary

The formation of new blood vessels from the pre-existing vasculature (angiogenesis) is a crucial stage in cancer progression and, indeed, angiogenesis inhibitors are now used as anticancer agents, clinically. Here we have explored the potential of flavonoid derivatives as antiangiogenic agents. Specifically, we have synthesised methoxy and 4-thio derivatives of the natural flavones quercetin and luteolin, two of which (4-thio quercetin and 4-thio luteolin) had never been previously reported. Seven of these compounds showed significant (P<0.05) antiangiogenic activity in an in vitro scratch assay. Their activity ranged from an 86% inhibition of the vascular endothelium growth factor (VEGF)-stimulated migration (observed for methoxyquercetin at 10 µM and for luteolin at 1 µM) to a 36% inhibition (for thiomethoxy quercetin at 10 µM). Western blotting studies showed that most (4 out of 7) compounds inhibited phosphorylation of the VEGF receptor-2 (VEGFR2), suggesting that the antiangiogenic activity was due to an interference with the VEGF/VEGFR2 pathway. Molecular modelling studies looking at the affinity of our compounds towards VEGFR and/or VEGF confirmed this hypothesis, and indeed the compound with the highest antiangiogenic activity (methoxyquercetin) showed the highest affinity towards VEGFR and VEGF. As reports from others have suggested that structurally similar compounds can elicit biological responses via a non-specific, promiscuous membrane perturbation, potential interactions of the active compounds with a model lipid bilayer were assessed via DSC. Luteolin and its derivatives did not perturb the model membrane even at concentrations 10 times higher than the biologically active concentration and only subtle interactions were observed for quercetin and its derivatives. Finally, cytotoxicity assessment of these flavonoid derivatives against MCF-7 breast cancer cells demonstrated also a direct anticancer activity albeit at generally higher concentrations than those required for an antiangiogenic effect (10 fold higher for the methoxy analogues). Taken together these results show promise for flavonoid derivatives as antiangiogenic agents.

Item Type:	Article
Refereed:	Yes
Divisions:	Interdisciplinary centres and themes > Chemical Analysis Facility (CAF) Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR) Life Sciences > School of Biological Sciences > Biomedical Sciences Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Medicinal Chemistry Research Group Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Pharmaceutics Research Group
ID Code:	40222
Uncontrolled Keywords:	Angiogenesis, flavones, quercetin, luteolin, antiangiogenic therapy
Publisher:	Elsevier

Download Statistics

Downloads

Downloads per month over past year

Altmetric

Deposit Details

References

[1] P. Carmeliet, R.K. Jain, Angiogenesis in cancer and other diseases., Nature. 407 (2000) 249–257. doi:10.1038/35025220. [2] D. Hanahan, J. Folkman, Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis, Cell. 86 (1996) 353–364. doi:10.1016/S0092-8674(00)80108-7. [3] D. Hanahan, The Hallmarks of Cancer, Cell. 100 (2000) 57–70. doi:10.1016/S0092-8674(00)81683-9. [4] D. Hanahan, R.A. Weinberg, Hallmarks of cancer: The next generation, Cell. 144 (2011) 646–674. doi:10.1016/j.cell.2011.02.013. [5] N. Ferrara, R.S. Kerbel, Angiogenesis as a therapeutic target., Nature. 438 (2005) 967–974. doi:10.1038/nature04483. [6] D. Ravishankar, A.K. Rajora, F. Greco, H.M.I. Osborn, Flavonoids as prospective compounds for anti-cancer therapy., Int. J. Biochem. Cell Biol. 45 (2013) 2821–31. doi:10.1016/j.biocel.2013.10.004. [7] A.M. Senderowicz, Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials., Invest. New Drugs. 17 (1999) 313–320. [8] S. Burdette-Radoux, R.G. Tozer, R.C. Lohmann, I. Quirt, D.S. Ernst, W. Walsh, et al., Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma, Invest. New Drugs. 22 (2004) 315–322. doi:10.1023/B:DRUG.0000026258.02846.1c. [9] J.A. Jones, A.S. Rupert, M. Poi, M.A. Phelps, L. Andritsos, R. Baiocchi, et al., Flavopiridol can be safely administered using a pharmacologically derived schedule and demonstrates activity in relapsed and refractory non-Hodgkin’s lymphoma, Am. J. Hematol. 89 (2014) 19–24. doi:10.1002/ajh.23568. [10] C. Loguercio, D. Festi, Silybin and the liver: from basic research to clinical practice., World J. Gastroenterol. 17 (2011) 2288–2301. doi:10.3748/wjg.v17.i18.2288. [11] D. Ferry, A. Smith, J. Malkhandi, Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition., Clin. Cancer Res. (1996) 659–668. http://clincancerres.aacrjournals.org/content/2/4/659.short (accessed October 7, 2014). [12] P.J. Mulholland, D.R. Ferry, D. Anderson, S.A. Hussain, A.M. Young, J.E. Cook, et al., Pre-clinical and clinical study of QC12, a water-soluble, pro-drug of quercetin, Ann. Oncol. 12 (2001) 245–248. doi:10.1023/A:1008372017097. [13] P. Pratheeshkumar, A. Budhraja, Y.O. Son, X. Wang, Z. Zhang, S. Ding, et al., Quercetin Inhibits Angiogenesis Mediated Human Prostate Tumor Growth by Targeting VEGFR- 2 Regulated AKT/mTOR/P70S6K Signaling Pathways, PLoS One. 7 (2012). doi:10.1371/journal.pone.0047516. [14] P. Pratheeshkumar, Y.-O. Son, A. Budhraja, X. Wang, S. Ding, L. Wang, et al., Luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis., PLoS One. 7 (2012) e52279. doi:10.1371/journal.pone.0052279. [15] N. Ferrara, H.-P. Gerber, J. LeCouter, The biology of VEGF and its receptors., Nat. Med. 9 (2003) 669–676. doi:10.1038/nm0603-669. [16] J.J. Wedge SR, VEGF receptor tyrosine kinase inhibitors for the treatment of cancer, in: Tumor Angiogenes. Basic Mech. Cancer Ther., N, ed., Springer, New York:, 2008: pp. 395–423. [17] S.A. Eccles, W. Court, L. Patterson, S. Sanderson, In vitro assays for endothelial cell functions related to angiogenesis: proliferation, motility, tubular differentiation, and proteolysis., Methods Mol. Biol. 467 (2009) 159–181. doi:10.1007/978-1-59745-241-0_9. [18] C.A. Staton, M.W.R. Reed, N.J. Brown, A critical analysis of current in vitro and in vivo angiogenesis assays, Int. J. Exp. Pathol. 90 (2009) 195–221. doi:10.1111/j.1365-2613.2008.00633.x. [19] L. Lamalice, F. Le Boeuf, J. Huot, Endothelial cell migration during angiogenesis, Circ. Res. 100 (2007) 782–794. doi:10.1161/01.RES.0000259593.07661.1e. [20] C.-C. Liang, A.Y. Park, J.-L. Guan, In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro., Nat. Protoc. 2 (2007) 329–333. doi:10.1038/nprot.2007.30. [21] M. Shibuya, Vegf-vegfr signals in health and disease, Biomol. Ther. 22 (2014) 1–9. doi:10.4062/biomolther.2013.113. [22] X. Li, L. Claesson-Welsh, M. Shibuya, VEGF receptor signal transduction., Methods Enzymol. 443 (2008) 261–284. doi:10.1016/S0076-6879(08)02013-2. [23] H.I. Ingólfsson, P. Thakur, K.F. Herold, E.A. Hobart, N.B. Ramsey, X. Periole, et al., Phytochemicals perturb membranes and promiscuously alter protein function., ACS Chem. Biol. 9 (2014) 1788–98. doi:10.1021/cb500086e. [24] R.A. Videira, M.C. Antunes-Madeira, V.M.C. Madeira, Perturbations induced by α- and β-endosulfan in lipid membranes: A DSC and fluorescence polarization study, Biochim. Biophys. Acta - Biomembr. 1419 (1999) 151–163. doi:10.1016/S0005-2736(99)00060-7. [25] R.L. Biltonen, D. Lichtenberg, The use of differential scanning calorimetry as a tool to characterize liposome preparations, Chem. Phys. Lipids. 64 (1993) 129–142. doi:10.1016/0009-3084(93)90062-8. [26] D. Bilge, I. Sahin, N. Kazanci, F. Severcan, Interactions of tamoxifen with distearoyl phosphatidylcholine multilamellar vesicles: FTIR and DSC studies, Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 130 (2014) 250–256. doi:http://dx.doi.org/10.1016/j.saa.2014.04.027. [27] B. Pawlikowska-Pawlȩga, H. Dziubińska, E. Król, K. Trȩbacz, A. Jarosz-Wilkołazka, R. Paduch, et al., Characteristics of quercetin interactions with liposomal and vacuolar membranes, Biochim. Biophys. Acta - Biomembr. 1838 (2014) 254–265. doi:10.1016/j.bbamem.2013.08.014. [28] B. Pawlikowska-Pawlega, W. Ignacy Gruszecki, L. Misiak, R. Paduch, T. Piersiak, B. Zarzyka, et al., Modification of membranes by quercetin, a naturally occurring flavonoid, via its incorporation in the polar head group, Biochim. Biophys. Acta - Biomembr. 1768 (2007) 2195–2204. doi:10.1016/j.bbamem.2007.05.027. [29] R. Sinha, M. Gadhwal, U. Joshi, S. Srivastava, G. Govil, Modifying effect of quercetin on model biomembranes: Studied by molecular dynamic simulation, DSC and NMR, Int J Curr Pharm Res. 4 (2012) 70–79. http://scholar.google.com/scholar?hl=en&btnG=Search&q=intitle:Modifying+effect+of+quercetin+on+model+biomembranes-studied+by+molecular+dynamic+simulation,+DSC+and+NMR#0 (accessed December 30, 2014). [30] T. Mosmann, Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays., J. Immunol. Methods. 65 (1983) 55–63. doi:10.1016/0022-1759(83)90303-4. [31] S.R. Wedge, J. Kendrew, L.F. Hennequin, P.J. Valentine, S.T. Barry, S.R. Brave, et al., AZD2171: A highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer, Cancer Res. 65 (2005) 4389–4400. doi:10.1158/0008-5472.CAN-04-4409. [32] A. Bagri, L. Berry, B. Gunter, M. Singh, I. Kasman, L.A. Damico, et al., Effects of anti-VEGF treatment duration on tumor growth, tumor regrowth, and treatment efficacy, Clin. Cancer Res. 16 (2010) 3887–3900. doi:10.1158/1078-0432.CCR-09-3100. [33] M.R. Mancuso, R. Davis, S.M. Norberg, S. O’Brien, B. Sennino, T. Nakahara, et al., Rapid vascular regrowth in tumors after reversal of VEGF inhibition, J. Clin. Invest. 116 (2006) 2610–2621. doi:10.1172/JCI24612. [34] J. Ma, D.J. Waxman, Combination of antiangiogenesis with chemotherapy for more effective cancer treatment., Mol. Cancer Ther. 7 (2008) 3670–3684. doi:10.1158/1535-7163.MCT-08-0715. [35] J. Yuan, I.L.K. Wong, T. Jiang, S.W. Wang, T. Liu, B. Jin Wen, et al., Synthesis of methylated quercetin derivatives and their reversal activities on P-gp- and BCRP-mediated multidrug resistance tumour cells, Eur. J. Med. Chem. 54 (2012) 413–422. doi:10.1016/j.ejmech.2012.05.026. [36] Ernst Bayer and Bruno Krämer, Synthese von Quercetylenderivaten, Chem. Ber. 97 (1964) 1057–1068. [37] M. Barontini, R. Bernini, F. Crisante, G. Fabrizi, Selective and efficient oxidative modifications of flavonoids with 2-iodoxybenzoic acid (IBX), Tetrahedron. 66 (2010) 6047–6053. doi:10.1016/j.tet.2010.06.014. [38] R.N. Yadava, U.K. Vishwakarma, New biologically active allelochemical from seeds of Cassia absus Linn ., Indian J. Chem., Sect B. 52 (2013) 953–957. [39] S.Y. Boateng, A.M. Seymour, N.S. Bhutta, M.J. Dunn, M.H. Yacoub, K.R. Boheler, Sub-antihypertensive doses of ramipril normalize sarcoplasmic reticulum calcium ATPase expression and function following cardiac hypertrophy in rats., J. Mol. Cell. Cardiol. 30 (1998) 2683–2694. doi:10.1006/jmcc.1998.0830. [40] A.N. Jain, Surflex : Fully Automatic Flexible Molecular Docking Using a Molecular Similarity-Based Search Engine Surflex : Fully Automatic Flexible Molecular Docking Using a Molecular, J. Med. Chem. 46 (2003) 499 –511. doi:10.1021/jm020406h. [41] Collaborative Computational Project, Number 4, “The CCP4 suite: programs for protein crystallography,” Acta Crystallogr., Sect. D Biol. Crystallogr. D50 (1994) 760–763. [42] R. Wang, Y. Lu, S. Wang, Comparative evaluation of 11 scoring functions for molecular docking, J. Med. Chem. 46 (2003) 2287–2303. doi:10.1021/jm0203783. [43] Y. Miyazaki, S. Matsunaga, J. Tang, Y. Maeda, M. Nakano, R.J. Philippe, et al., Novel 4-amino-furo[2,3-d]pyrimidines as Tie-2 and VEGFR2 dual inhibitors, Bioorganic Med. Chem. Lett. 15 (2005) 2203–2207. doi:10.1016/j.bmcl.2005.03.034. [44] C. Wiesmann, H.W. Christinger, A.G. Cochran, B.C. Cunningham, W.J. Fairbrother, C.J. Keenan, et al., Crystal structure of the complex between VEGF and a receptor-blocking peptide, Biochemistry. 37 (1998) 17765–17772. doi:10.1021/bi9819327. [45] M.J.D. Powell, Restart procedures for the conjugate gradient method, Math. Program. 12 (1977) 241–254. doi:10.1007/BF01593790. [46] W. DeLano, Pymol: An open-source molecular graphics tool, CCP4 Newsl. Protein Crystallogr. (2002). http://www.ccp4.ac.uk/newsletters/newsletter40.pdf#page=44. [47] L. Grell, C. Parkin, L. Slatest, P.A. Craig, EZ-Viz, a tool for simplifying molecular viewing in PyMOL, Biochem. Mol. Biol. Educ. 34 (2006) 402–407. doi:10.1002/bmb.2006.494034062672. [48] K. Cowtan, P. Emsley, K.S. Wilson, From crystal to structure with CCP4, Acta Crystallogr. Sect. D Biol. Crystallogr. 67 (2011) 233–234. doi:10.1107/S0907444911007578. [49] M.D. Winn, C.C. Ballard, K.D. Cowtan, E.J. Dodson, P. Emsley, P.R. Evans, et al., Overview of the CCP4 suite and current developments, Acta Crystallogr. Sect. D Biol. Crystallogr. 67 (2011) 235–242. doi:10.1107/S0907444910045749.

University Staff: Request a correction | Centaur Editors: Update this record

University of Reading

CentAUR: Central Archive at the University of Reading

Accessibility navigation

Exploring quercetin and luteolin derivatives as antiangiogenic agents

Abstract/Summary

Downloads

Page navigation

See also

Footer navigation