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Protein & Peptide Letters

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ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

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Research Article

VEGF165b Mutant Promotes the Apoptosis of Murine Breast Cancer Cells Induced by Paclitaxel by Inducing Tumor Vessel Maturation

Author(s): Chen Liang, Youwei Li, Enhui Guo, Shuge Bai, Yan Wang* and Huiyong Zhang*

Volume 30, Issue 11, 2023

Published on: 09 October, 2023

Page: [951 - 958] Pages: 8

DOI: 10.2174/0109298665256010230919062456

Price: $65

Abstract

Introduction: The anti-angiogenic agent vascular endothelial growth factor 165b (VEGF165b) mutant (mVEGF165b), which was developed by our laboratory, has superior antitumor activity to that of native VEGF165b; however, its mechanism of action and druggability need further exploration.

Methods: Using the commercial anti-angiogenic drug bevacizumab as a positive control, the mechanism and developability of mVEGF165b were evaluated and explored. The Cell Counting Kit-8 assay was performed to evaluate the effects of mVEGF165b and bevacizumab alone on the proliferation of human umbilical vein endothelial cells (HUVECs). Meanwhile, the inhibitory effects of mVEGF165b and bevacizumab combined with paclitaxel in a mouse model of breast cancer were assessed. Immunohistochemistry was used to detect their effects on tumor vascular maturation, and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to detect the apoptosis of tumor cells.

Results: In vitro cell experiments confirmed that mVEGF165b inhibited the proliferation of HUVECs with an efficacy equivalent to that of bevacizumab. mVEGF165b and bevacizumab combined with paclitaxel significantly delayed the growth of breast cancer in mice. Immunohistochemistry and the TUNEL assay showed that mVEGF165b and bevacizumab combined with paclitaxel-induced higher vascular maturity and more apoptosis than paclitaxel alone.

Conclusion: mVEGF165b showed similar efficacy and mechanism of action as bevacizumab, indicating its potential to be developed into a safe and effective anti-angiogenic drug.

Keywords: VEGF165b mutant, anti-angiogenic drug, bevacizumab, paclitaxel, breast cancer, vessel maturation.

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[1]
Quesada, A.R.; Muñoz-Chápuli, R.; Medina, M.A. Anti-angiogenic drugs: From bench to clinical trials. Med. Res. Rev., 2006, 26(4), 483-530.
[http://dx.doi.org/10.1002/med.20059] [PMID: 16652370]
[2]
Chen, H.X.; Cleck, J.N. Adverse effects of anticancer agents that target the VEGF pathway. Nat. Rev. Clin. Oncol., 2009, 6(8), 465-477.
[http://dx.doi.org/10.1038/nrclinonc.2009.94] [PMID: 19581909]
[3]
Moserle, L.; Jiménez-Valerio, G.; Casanovas, O. Antiangiogenic therapies: Going beyond their limits. Cancer Discov., 2014, 4(1), 31-41.
[http://dx.doi.org/10.1158/2159-8290.CD-13-0199] [PMID: 24356098]
[4]
Jayson, G.C.; Kerbel, R.; Ellis, L.M.; Harris, A.L. Antiangiogenic therapy in oncology: Current status and future directions. Lancet, 2016, 388(10043), 518-529.
[http://dx.doi.org/10.1016/S0140-6736(15)01088-0] [PMID: 26853587]
[5]
Dokun, A.O.; Annex, B.H. The VEGF165b “ICE-o-form” puts a chill on the VEGF story. Circ. Res., 2011, 109(3), 246-247.
[http://dx.doi.org/10.1161/CIRCRESAHA.111.249953] [PMID: 21778432]
[6]
Hua, J.; Spee, C.; Kase, S.; Rennel, E.S.; Magnussen, A.L.; Qiu, Y.; Varey, A.; Dhayade, S.; Churchill, A.J.; Harper, S.J.; Bates, D.O.; Hinton, D.R. Recombinant human VEGF165b inhibits experimental choroidal neovascularization. Invest. Ophthalmol. Vis. Sci., 2010, 51(8), 4282-4288.
[http://dx.doi.org/10.1167/iovs.09-4360] [PMID: 20237252]
[7]
Rennel, E.S.; Hamdollah-Zadeh, M.A.; Wheatley, E.R.; Magnussen, A.; Schüler, Y.; Kelly, S.P.; Finucane, C.; Ellison, D.; Cebe-Suarez, S.; Ballmer-Hofer, K.; Mather, S.; Stewart, L.; Bates, D.O.; Harper, S.J. Recombinant human VEGF165b protein is an effective anti-cancer agent in mice. Eur. J. Cancer, 2008, 44(13), 1883-1894.
[http://dx.doi.org/10.1016/j.ejca.2008.05.027] [PMID: 18657413]
[8]
Zhang, H.; Jia, E.; Xia, W.; Lu, C.; Zhu, W. VEGF165b mutant with a prolonged half-life and enhanced anti-tumor potency in a mouse model. J. Biotechnol., 2018, 284, 84-90.
[http://dx.doi.org/10.1016/j.jbiotec.2018.08.002] [PMID: 30134149]
[9]
Zhang, H.; Xia, W.; Liang, C.; Wang, X.; Zhi, L.; Guo, C.; Niu, Z.; Zhu, W. VEGF165b and its mutant demonstrate immunomodulatory, not merely anti-angiogenic functions, in tumor-bearing mice. Mol. Immunol., 2020, 122, 132-140.
[http://dx.doi.org/10.1016/j.molimm.2020.04.005] [PMID: 32353584]
[10]
Viallard, C.; Larrivée, B. Tumor angiogenesis and vascular normalization: Alternative therapeutic targets. Angiogenesis, 2017, 20(4), 409-426.
[http://dx.doi.org/10.1007/s10456-017-9562-9] [PMID: 28660302]
[11]
Tonissi, F.; Lattanzio, L.; Merlano, M.C.; Infante, L.; Lo Nigro, C.; Garrone, O. The effect of paclitaxel and nab-paclitaxel in combination with anti-angiogenic therapy in breast cancer cell lines. Invest. New Drugs, 2015, 33(4), 801-809.
[http://dx.doi.org/10.1007/s10637-015-0249-z] [PMID: 25947567]
[12]
Fujita, K.; Sano, D.; Kimura, M.; Yamashita, Y.; Kawakami, M.; Ishiguro, Y.; Nishimura, G.; Matsuda, H.; Tsukuda, M. Anti-tumor effects of bevacizumab in combination with paclitaxel on head and neck squamous cell carcinoma. Oncol. Rep., 2007, 18(1), 47-51.
[http://dx.doi.org/10.3892/or.18.1.47] [PMID: 17549344]
[13]
Rolny, C.; Mazzone, M.; Tugues, S.; Laoui, D.; Johansson, I.; Coulon, C.; Squadrito, M.L.; Segura, I.; Li, X.; Knevels, E.; Costa, S.; Vinckier, S.; Dresselaer, T.; Åkerud, P.; De Mol, M.; Salomäki, H.; Phillipson, M.; Wyns, S.; Larsson, E.; Buysschaert, I.; Botling, J.; Himmelreich, U.; Van Ginderachter, J.A.; De Palma, M.; Dewerchin, M.; Claesson-Welsh, L.; Carmeliet, P. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell, 2011, 19(1), 31-44.
[http://dx.doi.org/10.1016/j.ccr.2010.11.009] [PMID: 21215706]
[14]
Carter, J.J.; Wheal, A.J.; Hill, S.J.; Woolard, J. Effects of receptor tyrosine kinase inhibitors on VEGF165a- and VEGF165 b-stimulated gene transcription in HEK-293 cells expressing human VEGFR2. Br. J. Pharmacol., 2015, 172(12), 3141-3150.
[http://dx.doi.org/10.1111/bph.13116] [PMID: 25684635]
[15]
Chawla, N.; Kataria, S.; Aggarwal, K.; Chauhan, P.; Kumar, D. Significance of vascular endothelial growth factor and CD31 and morphometric analysis of microvessel density by CD31 receptor expression as an adjuvant tool in diagnosis of psoriatic lesions of skin. Indian J. Pathol. Microbiol., 2017, 60(2), 189-195.
[http://dx.doi.org/10.4103/IJPM.IJPM_862_15] [PMID: 28631633]
[16]
Kazemi, M.; Carrer, A.; Moimas, S.; Zandonà, L.; Bussani, R.; Casagranda, B.; Palmisano, S.; Prelazzi, P.; Giacca, M.; Zentilin, L.; De Manzini, N.; Giacca, M.; Zacchigna, S. VEGF121 and VEGF165 differentially promote vessel maturation and tumor growth in mice and humans. Cancer Gene Ther., 2016, 23(5), 125-132.
[http://dx.doi.org/10.1038/cgt.2016.12] [PMID: 27033458]
[17]
Bhattacharya, A.; Seshadri, M.; Oven, S.D.; Tóth, K.; Vaughan, M.M.; Rustum, Y.M. Tumor vascular maturation and improved drug delivery induced by methylselenocysteine leads to therapeutic synergy with anticancer drugs. Clin. Cancer Res., 2008, 14(12), 3926-3932.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-0212] [PMID: 18559614]
[18]
Li, S.; Zhang, Q.; Hong, Y. Tumor vessel normalization: a window to enhancing cancer immunotherapy. Technol. Cancer Res. Treat., 2020, 19.
[http://dx.doi.org/10.1177/1533033820980116] [PMID: 33287656]
[19]
Huinen, Z.R.; Huijbers, E.J.M.; van Beijnum, J.R.; Nowak-Sliwinska, P.; Griffioen, A.W. Anti-angiogenic agents — overcoming tumour endothelial cell anergy and improving immunotherapy outcomes. Nat. Rev. Clin. Oncol., 2021, 18(8), 527-540.
[http://dx.doi.org/10.1038/s41571-021-00496-y] [PMID: 33833434]
[20]
Garcia, J.; Hurwitz, H.I.; Sandler, A.B.; Miles, D.; Coleman, R.L.; Deurloo, R.; Chinot, O.L. Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat. Rev., 2020, 86, 102017.
[http://dx.doi.org/10.1016/j.ctrv.2020.102017] [PMID: 32335505]

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