Generic placeholder image

Current Protein & Peptide Science

Editor-in-Chief

ISSN (Print): 1389-2037
ISSN (Online): 1875-5550

Review Article

Biological Significance of EphB4 Expression in Cancer

Author(s): Asmat Ullah*, Anam Razzaq, Chuanzan Zhou, Najeeb Ullah, Somia Shehzadi, Tariq Aziz, Mohammad Y. Alfaifi, Serag Eldin I. Elbehairi and Haroon Iqbal*

Volume 25, Issue 3, 2024

Published on: 31 October, 2023

Page: [244 - 255] Pages: 12

DOI: 10.2174/0113892037269589231017055642

Price: $65

Abstract

Eph receptors and their Eph receptor-interacting (ephrin) ligands comprise a vital cell communication system with several functions. In cancer cells, there was evidence of bilateral Eph receptor signaling with both tumor-suppressing and tumor-promoting actions. As a member of the Eph receptor family, EphB4 has been linked to tumor angiogenesis, growth, and metastasis, which makes it a viable and desirable target for drug development in therapeutic applications. Many investigations have been conducted over the last decade to elucidate the structure and function of EphB4 in association with its ligand ephrinB2 for its involvement in tumorigenesis. Although several EphB4-targeting drugs have been investigated, and some selective inhibitors have been evaluated in clinical trials. This article addresses the structure and function of the EphB4 receptor, analyses its possibility as an anticancer therapeutic target, and summarises knowledge of EphB4 kinase inhibitors. To summarise, EphB4 is a difficult but potential treatment option for cancers.

Graphical Abstract

[1]
Unzue, A.; Lafleur, K.; Zhao, H.; Zhou, T.; Dong, J.; Kolb, P.; Liebl, J.; Zahler, S.; Caflisch, A.; Nevado, C. Three stories on Eph kinase inhibitors: From in silico discovery to in vivo validation. Eur. J. Med. Chem., 2016, 112, 347-366.
[http://dx.doi.org/10.1016/j.ejmech.2016.01.057] [PMID: 26907157]
[2]
Das, A.; Shergill, U.; Thakur, L.; Sinha, S.; Urrutia, R.; Mukhopadhyay, D.; Shah, V.H. Ephrin B2/EphB4 pathway in hepatic stellate cells stimulates Erk-dependent VEGF production and sinusoidal endothelial cell recruitment. Am. J. Physiol. Gastrointest. Liver Physiol., 2010, 298(6), G908-G915.
[http://dx.doi.org/10.1152/ajpgi.00510.2009] [PMID: 20338920]
[3]
Wu, B.; Rockel, J.S.; Lagares, D.; Kapoor, M. Ephrins and Eph receptor signaling in tissue repair and fibrosis. Curr. Rheumatol. Rep., 2019, 21(6), 23.
[http://dx.doi.org/10.1007/s11926-019-0825-x] [PMID: 30980212]
[4]
Pasquale, E.B. The Eph family of receptors. Curr. Opin. Cell Biol., 1997, 9(5), 608-615.
[http://dx.doi.org/10.1016/S0955-0674(97)80113-5] [PMID: 9330863]
[5]
Kania, A.; Klein, R. Mechanisms of ephrin–Eph signalling in development, physiology and disease. Nat. Rev. Mol. Cell Biol., 2016, 17(4), 240-256.
[http://dx.doi.org/10.1038/nrm.2015.16] [PMID: 26790531]
[6]
Psilopatis, I.; Karniadakis, I.; Danos, K.S.; Vrettou, K.; Michaelidou, K.; Mavridis, K.; Agelaki, S.; Theocharis, S. May EPH/Ephrin targeting revolutionize lung cancer treatment? Int. J. Mol. Sci., 2022, 24(1), 93.
[http://dx.doi.org/10.3390/ijms24010093] [PMID: 36613532]
[7]
Barquilla, A.; Pasquale, E.B. Eph receptors and ephrins: Therapeutic opportunities. Annu. Rev. Pharmacol. Toxicol., 2015, 55(1), 465-487.
[http://dx.doi.org/10.1146/annurev-pharmtox-011112-140226] [PMID: 25292427]
[8]
Chen, X.; Yu, D.; Zhou, H.; Zhang, X.; Hu, Y.; Zhang, R.; Gao, X.; lin, M.; Guo, T.; Zhang, K. The role of EphA7 in different tumors. Clin. Transl. Oncol., 2022, 24(7), 1274-1289.
[http://dx.doi.org/10.1007/s12094-022-02783-1] [PMID: 35112312]
[9]
Magic, Z.; Sandström, J.; Perez-Tenorio, G. Ephrin-B2 inhibits cell proliferation and motility in vitro and predicts longer metastasis-free survival in breast cancer. Int. J. Oncol., 2019, 55(6), 1275-1286.
[http://dx.doi.org/10.3892/ijo.2019.4892] [PMID: 31638179]
[10]
Piffko, A.; Uhl, C.; Vajkoczy, P.; Czabanka, M.; Broggini, T. EphrinB2–EphB4 signaling in neurooncological disease. Int. J. Mol. Sci., 2022, 23(3), 1679.
[http://dx.doi.org/10.3390/ijms23031679] [PMID: 35163601]
[11]
Du, E.; Li, X.; He, S.; Li, X.; He, S. The critical role of the interplays of EphrinB2/EphB4 and VEGF in the induction of angiogenesis. Mol. Biol. Rep., 2020, 47(6), 4681-4690.
[http://dx.doi.org/10.1007/s11033-020-05470-y] [PMID: 32488576]
[12]
Fan, W. B.; Zhao, J. N.; Bao, N. R. Effects of bidirectional EphB4-EphrinB2 signaling on bone remodeling. China J. Orthopaed. Traumatol., 2013, 26(8), 705-8.
[13]
Groppa, E.; Brkic, S.; Uccelli, A.; Wirth, G.; Korpisalo-Pirinen, P.; Filippova, M.; Dasen, B.; Sacchi, V.; Muraro, M.G.; Trani, M.; Reginato, S.; Gianni-Barrera, R.; Ylä-Herttuala, S.; Banfi, A. EphrinB2/EphB4 signaling regulates non-sprouting angiogenesis by VEGF. EMBO Rep., 2018, 19(5), e45054.
[http://dx.doi.org/10.15252/embr.201745054] [PMID: 29643120]
[14]
Gong, T.; Xu, J.; Heng, B.; Qiu, S.; Yi, B.; Han, Y.; Lo, E.C.M.; Zhang, C. EphrinB2/EphB4 signaling regulates DPSCs to induce sprouting angiogenesis of endothelial cells. J. Dent. Res., 2019, 98(7), 803-812.
[http://dx.doi.org/10.1177/0022034519843886] [PMID: 31017515]
[15]
Bhatia, S.; Nguyen, D.; Darragh, L.B.; Van Court, B.; Sharma, J.; Knitz, M.W.; Piper, M.; Bukkapatnam, S.; Gadwa, J.; Bickett, T.E.; Bhuvane, S.; Corbo, S.; Wu, B.; Lee, Y.; Fujita, M.; Joshi, M.; Heasley, L.E.; Ferris, R.L.; Rodriguez, O.; Albanese, C.; Kapoor, M.; Pasquale, E.B.; Karam, S.D. EphB4 and ephrinB2 act in opposition in the head and neck tumor microenvironment. Nat. Commun., 2022, 13(1), 3535.
[http://dx.doi.org/10.1038/s41467-022-31124-7] [PMID: 35725568]
[16]
Pasquale, E.B. Eph receptors and ephrins in cancer: Bidirectional signalling and beyond. Nat. Rev. Cancer, 2010, 10(3), 165-180.
[http://dx.doi.org/10.1038/nrc2806] [PMID: 20179713]
[17]
Venkitachalam, S.; Babu, D.; Ravillah, D.; Katabathula, R.M.; Joseph, P.; Singh, S.; Udhayakumar, B.; Miao, Y.; Martinez-Uribe, O.; Hogue, J.A.; Kresak, A.M.; Dawson, D.; LaFramboise, T.; Willis, J.E.; Chak, A.; Garman, K.S.; Blum, A.E.; Varadan, V.; Guda, K. The Ephrin B2 receptor tyrosine kinase is a regulator of proto-oncogene MYC and molecular programs central to Barrett’s neoplasia. Gastroenterology, 2022, 163(5), 1228-1241.
[http://dx.doi.org/10.1053/j.gastro.2022.07.045] [PMID: 35870513]
[18]
de Boer, E.C.W.; van Gils, J.M.; van Gils, M.J. Ephrin-Eph signaling usage by a variety of viruses. Pharmacol. Res., 2020, 159, 105038.
[http://dx.doi.org/10.1016/j.phrs.2020.105038] [PMID: 32565311]
[19]
Arcas, A.; Wilkinson, D.G.; Nieto, M.Á. The evolutionary history of Ephs and Ephrins: Toward multicellular organisms. Mol. Biol. Evol., 2020, 37(2), 379-394.
[http://dx.doi.org/10.1093/molbev/msz222] [PMID: 31589243]
[20]
Bennett, B.D.; Wang, Z.; Kuang, W.J.; Wang, A.; Groopman, J.E.; Goeddel, D.V.; Scadden, D.T. Cloning and characterization of HTK, a novel transmembrane tyrosine kinase of the EPH subfamily. J. Biol. Chem., 1994, 269(19), 14211-14218.
[http://dx.doi.org/10.1016/S0021-9258(17)36776-5] [PMID: 8188704]
[21]
Chen, Y.; Zhang, H.; Zhang, Y. Targeting receptor tyrosine kinase EphB4 in cancer therapy. Semin. Cancer Biol., 2019, 56, 37-46.
[http://dx.doi.org/10.1016/j.semcancer.2017.10.002] [PMID: 28993206]
[22]
Salgia, R.; Kulkarni, P.; Gill, P.S. EphB4: A promising target for upper aerodigestive malignancies. Biochim. Biophys. Acta Rev. Cancer, 2018, 1869(2), 128-137.
[http://dx.doi.org/10.1016/j.bbcan.2018.01.003] [PMID: 29369779]
[23]
Wu, D.; Zhang, X.; Liu, Z.; Yan, H.; Mai, J.; Zhao, Z.; Zhong, Q.; Liu, X. Decreased expression of protein tyrosine kinase 6 contributes to tumor progression and metastasis in laryngeal squamous cell carcinoma. Biochem. Biophys. Res. Commun., 2018, 503(3), 1378-1384.
[http://dx.doi.org/10.1016/j.bbrc.2018.07.051] [PMID: 30029880]
[24]
Roskoski, R., Jr Ibrutinib inhibition of Bruton protein-tyrosine kinase (BTK) in the treatment of B cell neoplasms. Pharmacological research, 2016, 113(Pt A), 395-408.
[25]
Wang, E.; Mi, X.; Thompson, M.C.; Montoya, S.; Notti, R.Q.; Afaghani, J.; Durham, B.H.; Penson, A.; Witkowski, M.T.; Lu, S.X.; Bourcier, J.; Hogg, S.J.; Erickson, C.; Cui, D.; Cho, H.; Singer, M.; Totiger, T.M.; Chaudhry, S.; Geyer, M.; Alencar, A.; Linley, A.J.; Palomba, M.L.; Coombs, C.C.; Park, J.H.; Zelenetz, A.; Roeker, L.; Rosendahl, M.; Tsai, D.E.; Ebata, K.; Brandhuber, B.; Hyman, D.M.; Aifantis, I.; Mato, A.; Taylor, J.; Abdel-Wahab, O. Mechanisms of resistance to noncovalent Bruton’s tyrosine kinase inhibitors. N. Engl. J. Med., 2022, 386(8), 735-743.
[http://dx.doi.org/10.1056/NEJMoa2114110] [PMID: 35196427]
[26]
Zhang, L.; Shan, Y.; Ji, X.; Zhu, M.; Li, C.; Sun, Y.; Si, R.; Pan, X.; Wang, J.; Ma, W.; Dai, B.; Wang, B.; Zhang, J. Discovery and evaluation of triple inhibitors of VEGFR-2, TIE-2 and EphB4 as anti-angiogenic and anti-cancer agents. Oncotarget, 2017, 8(62), 104745-104760.
[http://dx.doi.org/10.18632/oncotarget.20065] [PMID: 29285210]
[27]
Pan, X.; Liang, L.; Si, R.; Wang, J.; Zhang, Q.; Zhou, H.; Zhang, L.; Zhang, J. Discovery of novel anti-angiogenesis agents. Part 10: Multi-target inhibitors of VEGFR-2, Tie-2 and EphB4 incorporated with 1,2,3-triazol. Eur. J. Med. Chem., 2019, 163, 1-9.
[http://dx.doi.org/10.1016/j.ejmech.2018.11.042] [PMID: 30503935]
[28]
Kumar, S.R.; Scehnet, J.S.; Ley, E.J.; Singh, J.; Krasnoperov, V.; Liu, R.; Manchanda, P.K.; Ladner, R.D.; Hawes, D.; Weaver, F.A.; Beart, R.W.; Singh, G.; Nguyen, C.; Kahn, M.; Gill, P.S. Preferential induction of EphB4 over EphB2 and its implication in colorectal cancer progression. Cancer Res., 2009, 69(9), 3736-3745.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-3232] [PMID: 19366806]
[29]
Hu, F.; Tao, Z.; Shen, Z.; Wang, X.; Hua, F. Down-regulation of EphB4 phosphorylation is necessary for esophageal squamous cell carcinoma tumorigenecity. Tumour Biol., 2014, 35(7), 7225-7232.
[http://dx.doi.org/10.1007/s13277-014-1955-4] [PMID: 24771266]
[30]
Bai, J.; Wang, Y.; Liu, L.; Zhao, Y. Ephrin B2 and EphB4 selectively mark arterial and venous vessels in cerebral arteriovenous malformation. J. Int. Med. Res., 2014, 42(2), 405-415.
[http://dx.doi.org/10.1177/0300060513478091] [PMID: 24517927]
[31]
Liersch-Löhn, B.; Slavova, N.; Buhr, H.J.; Bennani-Baiti, I.M. Differential protein expression and oncogenic gene network link tyrosine kinase ephrin B4 receptor to aggressive gastric and gastroesophageal junction cancers. Int. J. Cancer, 2016, 138(5), 1220-1231.
[http://dx.doi.org/10.1002/ijc.29865] [PMID: 26414866]
[32]
Nguyen, T.M.; Arthur, A.; Hayball, J.D.; Gronthos, S. EphB and Ephrin-B interactions mediate human mesenchymal stem cell suppression of activated T-cells. Stem Cells Dev., 2013, 22(20), 2751-2764.
[http://dx.doi.org/10.1089/scd.2012.0676] [PMID: 23711177]
[33]
Becerikli, M.; Merwart, B.; Lam, M.C.; Suppelna, P.; Rittig, A.; Mirmohammedsadegh, A.; Stricker, I.; Theiss, C.; Singer, B.B.; Jacobsen, F.; Steinstraesser, L. EPHB4 tyrosine-kinase receptor expression and biological significance in soft tissue sarcoma. Int. J. Cancer, 2015, 136(8), 1781-1791.
[http://dx.doi.org/10.1002/ijc.29244] [PMID: 25274141]
[34]
Nanamiya, R.; Saito-Koyama, R.; Miki, Y.; Inoue, C.; Asavasupreechar, T.; Abe, J.; Sato, I.; Sasano, H. EphB4 as a novel target for the EGFR-independent suppressive effects of osimertinib on cell cycle progression in non-small cell lung cancer. Int. J. Mol. Sci., 2021, 22(16), 8522.
[http://dx.doi.org/10.3390/ijms22168522] [PMID: 34445227]
[35]
Noren, N.K.; Yang, N.Y.; Silldorff, M.; Mutyala, R.; Pasquale, E.B. Ephrin-independent regulation of cell substrate adhesion by the EphB4 receptor. Biochem. J., 2009, 422(3), 433-442.
[http://dx.doi.org/10.1042/BJ20090014] [PMID: 19552627]
[36]
Noren, N.K.; Foos, G.; Hauser, C.A.; Pasquale, E.B. The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl–Crk pathway. Nat. Cell Biol., 2006, 8(8), 815-825.
[http://dx.doi.org/10.1038/ncb1438] [PMID: 16862147]
[37]
Noren, N.K.; Pasquale, E.B. Paradoxes of the EphB4 receptor in cancer. Cancer Res., 2007, 67(9), 3994-3997.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-0525] [PMID: 17483308]
[38]
Xiao, Z.; Carrasco, R.; Kinneer, K.; Sabol, D.; Jallal, B.; Coats, S.; Tice, D.A. EphB4 promotes or suppresses Ras/MEK/ERK pathway in a context-dependent manner. Cancer Biol. Ther., 2012, 13(8), 630-637.
[http://dx.doi.org/10.4161/cbt.20080] [PMID: 22555806]
[39]
Arvanitis, D.; Davy, A. Eph/ephrin signaling: Networks. Genes Dev., 2008, 22(4), 416-429.
[http://dx.doi.org/10.1101/gad.1630408] [PMID: 18281458]
[40]
Meyer, S.; Hafner, C.; Guba, M.; Flegel, S.; Geissler, E.; Becker, B.; Koehl, G.; Orsó, E.; Landthaler, M.; Vogt, T. ephrin-B2 overexpression enhances integrin-mediated ECM-attachment and migration of B16 melanoma cells. Int. J. Oncol., 2005, 27(5), 1197-1206.
[http://dx.doi.org/10.3892/ijo.27.5.1197] [PMID: 16211213]
[41]
Nakada, M.; Anderson, E.M.; Demuth, T.; Nakada, S.; Reavie, L.B.; Drake, K.L.; Hoelzinger, D.B.; Berens, M.E. The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion. Int. J. Cancer, 2010, 126(5), 1155-1165.
[PMID: 19728339]
[42]
Noren, N.K.; Lu, M.; Freeman, A.L.; Koolpe, M.; Pasquale, E.B. Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth. Proc. Natl. Acad. Sci. USA, 2004, 101(15), 5583-5588.
[http://dx.doi.org/10.1073/pnas.0401381101] [PMID: 15067119]
[43]
Psilopatis, I.; Souferi-Chronopoulou, E.; Vrettou, K.; Troungos, C.; Theocharis, S. EPH/Ephrin-targeting treatment in breast cancer: A new chapter in breast cancer therapy. Int. J. Mol. Sci., 2022, 23(23), 15275.
[http://dx.doi.org/10.3390/ijms232315275] [PMID: 36499598]
[44]
Sawamiphak, S.; Seidel, S.; Essmann, C.L.; Wilkinson, G.A.; Pitulescu, M.E.; Acker, T.; Acker-Palmer, A. Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature, 2010, 465(7297), 487-491.
[http://dx.doi.org/10.1038/nature08995] [PMID: 20445540]
[45]
Alam, S.K.; Yadav, V.K.; Bajaj, S.; Datta, A.; Dutta, S.K.; Bhattacharyya, M.; Bhattacharya, S.; Debnath, S.; Roy, S.; Boardman, L.A.; Smyrk, T.C.; Molina, J.R.; Chakrabarti, S.; Chowdhury, S.; Mukhopadhyay, D.; Roychoudhury, S. DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53. Cell Death Differ., 2016, 23(4), 707-722.
[http://dx.doi.org/10.1038/cdd.2015.133] [PMID: 26494468]
[46]
Takahashi, Y.; Itoh, M.; Nara, N.; Tohda, S. Effect of EPH-ephrin signaling on the growth of human leukemia cells. Anticancer Res., 2014, 34(6), 2913-2918.
[PMID: 24922654]
[47]
Lv, J.; Xia, Q.; Wang, J.; Shen, Q.; Zhang, J.; Zhou, X. EphB4 promotes the proliferation, invasion, and angiogenesis of human colorectal cancer. Exp. Mol. Pathol., 2016, 100(3), 402-408.
[http://dx.doi.org/10.1016/j.yexmp.2016.03.011] [PMID: 27072105]
[48]
Brantley-Sieders, D.M.; Jiang, A.; Sarma, K.; Badu-Nkansah, A.; Walter, D.L.; Shyr, Y.; Chen, J. Eph/ephrin profiling in human breast cancer reveals significant associations between expression level and clinical outcome. PLoS One, 2011, 6(9), e24426.
[http://dx.doi.org/10.1371/journal.pone.0024426] [PMID: 21935409]
[49]
Ferguson, B.D.; Liu, R.; Rolle, C.E.; Tan, Y.H.C.; Krasnoperov, V.; Kanteti, R.; Tretiakova, M.S.; Cervantes, G.M.; Hasina, R.; Hseu, R.D.; Iafrate, A.J.; Karrison, T.; Ferguson, M.K.; Husain, A.N.; Faoro, L.; Vokes, E.E.; Gill, P.S.; Salgia, R. The EphB4 receptor tyrosine kinase promotes lung cancer growth: A potential novel therapeutic target. PLoS One, 2013, 8(7), e67668.
[http://dx.doi.org/10.1371/journal.pone.0067668] [PMID: 23844053]
[50]
Liu, R.; Ferguson, B.D.; Zhou, Y.; Naga, K.; Salgia, R.; Gill, P.S.; Krasnoperov, V. EphB4 as a therapeutic target in mesothelioma. BMC Cancer, 2013, 13(1), 269.
[http://dx.doi.org/10.1186/1471-2407-13-269] [PMID: 23721559]
[51]
Yang, N.Y.; Pasquale, E.B.; Owen, L.B.; Ethell, I.M. The EphB4 receptor-tyrosine kinase promotes the migration of melanoma cells through Rho-mediated actin cytoskeleton reorganization. J. Biol. Chem., 2006, 281(43), 32574-32586.
[http://dx.doi.org/10.1074/jbc.M604338200] [PMID: 16950769]
[52]
Hasina, R.; Kanade, G.; Yala, S.; Mollberg, N.; Muller, J.; Surati, M.; Kanteti, R.; Husain, A.; Posner, M.; Waxman, I.; Vigneswaran, W.; Ferguson, M.; Villaflor, V.; Vokes, E.E.; Gill, P.; Salgia, R. Abstract 1625: Role of EphB4 in esophageal cancer: Expression, amplification, and therapeutic inhibition. Cancer Res., 2011, 71(8_Supplement)(Suppl.), 1625-1625.
[http://dx.doi.org/10.1158/1538-7445.AM2011-1625]
[53]
Ma, X.; Luo, D.; Li, K.; Liu, R.; Liu, Y.; Zhu, T.; Deng, D.; Zhou, J.; Meng, L.; Wang, S.; Ma, D. Suppression of EphB4 improves the inhibitory effect of mTOR shRNA on the biological behaviors of ovarian cancer cells by down-regulating Akt phosphorylation. J. Huazhong Univ. Sci. Technolog. Med. Sci., 2012, 32(3), 358-363.
[http://dx.doi.org/10.1007/s11596-012-0062-2] [PMID: 22684558]
[54]
Huang, G.; Li, M. The role of EphB4 and IGF-IR expression in breast cancer cells. Int. J. Clin. Exp. Pathol., 2015, 8(5), 5997-6004.
[PMID: 26191333]
[55]
Mertens-Walker, I.; Fernandini, B.C.; Maharaj, M.S.N.; Rockstroh, A.; Nelson, C.C.; Herington, A.C.; Stephenson, S.A. The tumour-promoting receptor tyrosine kinase, EphB4, regulates expression of Integrin-β8 in prostate cancer cells. BMC Cancer, 2015, 15(1), 164.
[http://dx.doi.org/10.1186/s12885-015-1164-6] [PMID: 25886373]
[56]
Li, M.; Zhao, Z. Clinical implications of EphB4 receptor expression in pancreatic cancer. Mol. Biol. Rep., 2013, 40(2), 1735-1741.
[http://dx.doi.org/10.1007/s11033-012-2224-5] [PMID: 23079712]
[57]
Li, M.; Zhao, J.; Qiao, J.; Song, C.; Zhao, Z. EphB4 regulates the growth and migration of pancreatic cancer cells. Tumour Biol., 2014, 35(7), 6855-6859.
[http://dx.doi.org/10.1007/s13277-014-1937-6] [PMID: 25051915]
[58]
Sarwar, A.; Zhu, Z.; Zhu, M.; Tang, X.; Su, Q.; Yang, T.; Tang, W.; Zhang, Y. Homoharringtonine sensitizes pancreatic cancer to erlotinib by direct targeting and miRNA-130b-3p-mediated EphB4-JAK2-STAT3 axis. J. Pharm. Pharmacol., 2023, rgad055.
[http://dx.doi.org/10.1093/jpp/rgad055] [PMID: 37463100]
[59]
Alonso-C, L.M.; Trinidad, E.M.; de Garcillan, B.; Ballesteros, M.; Castellanos, M.; Cotillo, I.; Muñoz, J.J.; Zapata, A.G. Expression profile of Eph receptors and ephrin ligands in healthy human B lymphocytes and chronic lymphocytic leukemia B-cells. Leuk. Res., 2009, 33(3), 395-406.
[http://dx.doi.org/10.1016/j.leukres.2008.08.010] [PMID: 18819711]
[60]
Wrobel, T.; Pogrzeba, J.; Stefanko, E.; Wojtowicz, M.; Jazwiec, B.; Dzietczenia, J.; Mazur, G.; Kuliczkowski, K. Expression of Eph A4, Eph B2 and Eph B4 receptors in AML. Pathology oncology research. Pathol. Oncol. Res., 2014, 20(4), 901-907.
[http://dx.doi.org/10.1007/s12253-014-9767-9] [PMID: 24764074]
[61]
Krasnoperov, V.; Kumar, S.R.; Ley, E.; Li, X.; Scehnet, J.; Liu, R.; Zozulya, S.; Gill, P.S. Novel EphB4 monoclonal antibodies modulate angiogenesis and inhibit tumor growth. Am. J. Pathol., 2010, 176(4), 2029-2038.
[http://dx.doi.org/10.2353/ajpath.2010.090755] [PMID: 20133814]
[62]
Huang, B.T.; Zeng, Q.C.; Zhao, W.H.; Tan, Y. Homoharringtonine contributes to imatinib sensitivity by blocking the EphB4/RhoA pathway in chronic myeloid leukemia cell lines. Med. Oncol., 2014, 31(2), 836.
[http://dx.doi.org/10.1007/s12032-013-0836-9] [PMID: 24415355]
[63]
Wang, Q.; Ding, W.; Ding, Y.; Ma, J.; Qian, Z.; Shao, J.; Li, Y. Homoharringtonine suppresses imatinib resistance via the Bcl-6/p53 pathway in chronic myeloid leukemia cell lines. Oncotarget, 2017, 8(23), 37594-37604.
[http://dx.doi.org/10.18632/oncotarget.16731] [PMID: 28410239]
[64]
Zhang, J.F.; Xu, N.; Du, Q.F.; Li, R.; Liu, X.L. EphB4-VAV1 signaling pathway is associated with imatinib resistance in chronic myeloid leukemia cells. Blood Cells Mol. Dis., 2016, 59, 58-62.
[http://dx.doi.org/10.1016/j.bcmd.2016.04.007] [PMID: 27282569]
[65]
Zhao, W.H.; Huang, B.T.; Zhang, J.Y.; Zeng, Q.C. Distinct EphB4-mediated mechanisms of apoptotic and resistance to dasatinib in human chronic myeloid leukemia and K562 cell lines. Leuk. Res., 2017, 63, 28-33.
[http://dx.doi.org/10.1016/j.leukres.2017.10.014] [PMID: 29096333]
[66]
Gu, S.; Fu, W.Y.; Fu, A.K.Y.; Tong, E.P.S.; Ip, F.C.F.; Huang, X.; Ip, N.Y. Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs. Sci. Rep., 2018, 8(1), 7377.
[http://dx.doi.org/10.1038/s41598-018-25790-1] [PMID: 29743517]
[67]
Jarkowski, A., III; Sweeney, R.P. Nilotinib: A new tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia. Pharmacotherapy, 2008, 28(11), 1374-1382.
[http://dx.doi.org/10.1592/phco.28.11.1374] [PMID: 18956997]
[68]
Chmielecki, J.; Pietanza, M.C.; Aftab, D.; Shen, R.; Zhao, Z.; Chen, X.; Hutchinson, K.; Viale, A.; Kris, M.G.; Stout, T.; Miller, V.; Rizvi, N.; Pao, W. EGFR-mutant lung adenocarcinomas treated first-line with the novel EGFR inhibitor, XL647, can subsequently retain moderate sensitivity to erlotinib. J. Thorac. Oncol., 2012, 7(2), 434-442.
[http://dx.doi.org/10.1097/JTO.0b013e31823c5aee] [PMID: 22173702]
[69]
Unzue, A.; Dong, J.; Lafleur, K.; Zhao, H.; Frugier, E.; Caflisch, A.; Nevado, C. Pyrrolo[3,2-b]quinoxaline derivatives as types I1/2 and II Eph tyrosine kinase inhibitors: structure-based design, synthesis, and in vivo validation. J. Med. Chem., 2014, 57(15), 6834-6844.
[http://dx.doi.org/10.1021/jm5009242] [PMID: 25076195]
[70]
Giorgio, C.; Hassan Mohamed, I.; Flammini, L.; Barocelli, E.; Incerti, M.; Lodola, A.; Tognolini, M. Lithocholic acid is an Eph-ephrin ligand interfering with Eph-kinase activation. PLoS One, 2011, 6(3), e18128.
[http://dx.doi.org/10.1371/journal.pone.0018128] [PMID: 21479221]
[71]
Hassan-Mohamed, I.; Giorgio, C.; Incerti, M.; Russo, S.; Pala, D.; Pasquale, E.B.; Zanotti, I.; Vicini, P.; Barocelli, E.; Rivara, S.; Mor, M.; Lodola, A.; Tognolini, M. UniPR129 is a competitive small molecule Eph-ephrin antagonist blocking in vitro angiogenesis at low micromolar concentrations. Br. J. Pharmacol., 2014, 171(23), 5195-5208.
[http://dx.doi.org/10.1111/bph.12669] [PMID: 24597515]
[72]
Mitchell, S.A.; Danca, M.D.; Blomgren, P.A.; Darrow, J.W.; Currie, K.S.; Kropf, J.E.; Lee, S.H.; Gallion, S.L.; Xiong, J.M.; Pippin, D.A.; DeSimone, R.W.; Brittelli, D.R.; Eustice, D.C.; Bourret, A.; Hill-Drzewi, M.; Maciejewski, P.M.; Elkin, L.L. Imidazo[1,2-a]pyrazine diaryl ureas: Inhibitors of the receptor tyrosine kinase EphB4. Bioorg. Med. Chem. Lett., 2009, 19(24), 6991-6995.
[http://dx.doi.org/10.1016/j.bmcl.2009.10.037] [PMID: 19879134]
[73]
Nakazawa, Y.; Kawano, S.; Matsui, J.; Funahashi, Y.; Tohyama, O.; Muto, H.; Nakagawa, T.; Matsushima, T. Multitargeting strategy using lenvatinib and golvatinib: Maximizing anti-angiogenesis activity in a preclinical cancer model. Cancer Sci., 2015, 106(2), 201-207.
[http://dx.doi.org/10.1111/cas.12581] [PMID: 25458359]
[74]
Zhu, M.; Gong, Z.; Wu, Q.; Su, Q.; Yang, T.; Yu, R.; Xu, R.; Zhang, Y. Homoharringtonine suppresses tumor proliferation and migration by regulating EphB4-mediated β-catenin loss in hepatocellular carcinoma. Cell Death Dis., 2020, 11(8), 632.
[http://dx.doi.org/10.1038/s41419-020-02902-2] [PMID: 32801343]
[75]
Shi, X.; Zhu, M.; Gong, Z.; Yang, T.; Yu, R.; Wang, J.; Zhang, Y. Homoharringtonine suppresses LoVo cell growth by inhibiting EphB4 and the PI3K/AKT and MAPK/EKR1/2 signaling pathways. Food Chem. Toxicol., 2020, 136, 110960.
[http://dx.doi.org/10.1016/j.fct.2019.110960] [PMID: 31726078]
[76]
Su, Q.; Wang, J.; Wu, Q.; Ullah, A.; Ghauri, M.A.; Sarwar, A.; Chen, L.; Liu, F.; Zhang, Y. Sanguinarine combats hypoxia-induced activation of EphB4 and HIF-1α pathways in breast cancer. Phytomedicine, 2021, 84, 153503.
[http://dx.doi.org/10.1016/j.phymed.2021.153503] [PMID: 33636580]
[77]
Zhu, M.; Cui, Y.; Yang, L.; Yang, T.; Wang, H.; Zhang, D.; Ma, W.; Zhang, Y. Ephrin type-B receptor 4 affinity chromatography: An effective and rapid method studying the active compounds targeting Ephrin type-B receptor 4. J. Chromatogr. A, 2019, 1586, 82-90.
[http://dx.doi.org/10.1016/j.chroma.2018.12.005] [PMID: 30545684]
[78]
Xiong, C.; Wen, Y.; Zhao, J.; Yin, D.; Xu, L.; Chelariu-Raicu, A.; Yao, C.; Leng, X.; Liu, J.; Chaudhari, R.R.; Zhang, S.; Sood, A.K.; Li, C. Targeting forward and reverse EphB4/EFNB2 signaling by a peptide with dual functions. Sci. Rep., 2020, 10(1), 520.
[http://dx.doi.org/10.1038/s41598-020-57477-x] [PMID: 31949258]
[79]
Liu, S.; Li, D.; Park, R.; Liu, R.; Xia, Z.; Guo, J.; Krasnoperov, V.; Gill, P.S.; Li, Z.; Shan, H.; Conti, P.S. PET imaging of colorectal and breast cancer by targeting EphB4 receptor with 64Cu-labeled hAb47 and hAb131 antibodies. J. Nucl. Med., 2013, 54(7), 1094-1100.
[http://dx.doi.org/10.2967/jnumed.112.116822] [PMID: 23667241]
[80]
Ma, W.; Zhu, M.; Zhang, D.; Yang, L.; Yang, T.; Li, X.; Zhang, Y. Berberine inhibits the proliferation and migration of breast cancer ZR-75-30 cells by targeting Ephrin-B2. Phytomedicine, 2017, 25, 45-51.
[http://dx.doi.org/10.1016/j.phymed.2016.12.013] [PMID: 28190470]
[81]
Ma, W.; Zhu, M.; Yang, L.; Yang, T.; Zhang, Y. Synergistic effect of TPD7 and berberine against leukemia jurkat cell growth through regulating Ephrin-B2 signaling. Phytother. Res., 2017, 31(9), 1392-1399.
[http://dx.doi.org/10.1002/ptr.5866] [PMID: 28703366]
[82]
Martiny-Baron, G.; Holzer, P.; Billy, E.; Schnell, C.; Brueggen, J.; Ferretti, M.; Schmiedeberg, N.; Wood, J.M.; Furet, P.; Imbach, P. The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis. Angiogenesis, 2010, 13(3), 259-267.
[http://dx.doi.org/10.1007/s10456-010-9183-z] [PMID: 20803239]
[83]
Fan, T.; Liang, B.; Nie, L.; Wang, J.; Zhang, H.; Ciechanover, A.; Xu, Y.; An, J.; Huang, Z. A synthetic bivalent peptide ligand of EphB4 with potent agonistic activity. Eur. J. Med. Chem., 2022, 244, 114804.
[http://dx.doi.org/10.1016/j.ejmech.2022.114804] [PMID: 36208510]
[84]
Bardelle, C.; Barlaam, B.; Brooks, N.; Coleman, T.; Cross, D.; Ducray, R.; Green, I.; Brempt, C.L.; Olivier, A.; Read, J. Inhibitors of the tyrosine kinase EphB4. Part 3: Identification of non-benzodioxole-based kinase inhibitors. Bioorg. Med. Chem. Lett., 2010, 20(21), 6242-6245.
[http://dx.doi.org/10.1016/j.bmcl.2010.08.100] [PMID: 20850301]
[85]
Bardelle, C.; Coleman, T.; Cross, D.; Davenport, S.; Kettle, J.G.; Ko, E.J.; Leach, A.G.; Mortlock, A.; Read, J.; Roberts, N.J.; Robins, P.; Williams, E.J. Inhibitors of the tyrosine kinase EphB4. Part 2: Structure-based discovery and optimisation of 3,5-bis substituted anilinopyrimidines. Bioorg. Med. Chem. Lett., 2008, 18(21), 5717-5721.
[http://dx.doi.org/10.1016/j.bmcl.2008.09.087] [PMID: 18851911]
[86]
Chen, Y.; Zhang, Y. Functional and mechanistic analysis of telomerase: An antitumor drug target. Pharmacol. Ther., 2016, 163, 24-47.
[http://dx.doi.org/10.1016/j.pharmthera.2016.03.017] [PMID: 27118336]
[87]
Bardelle, C.; Cross, D.; Davenport, S.; Kettle, J.G.; Ko, E.J.; Leach, A.G.; Mortlock, A.; Read, J.; Roberts, N.J.; Robins, P.; Williams, E.J. Inhibitors of the tyrosine kinase EphB4. Part 1: Structure-based design and optimization of a series of 2,4-bis-anilinopyrimidines. Bioorg. Med. Chem. Lett., 2008, 18(9), 2776-2780.
[http://dx.doi.org/10.1016/j.bmcl.2008.04.015] [PMID: 18434142]
[88]
Barlaam, B.; Ducray, R.; Brempt, C.L.; Plé, P.; Bardelle, C.; Brooks, N.; Coleman, T.; Cross, D.; Kettle, J.G.; Read, J. Inhibitors of the tyrosine kinase EphB4. Part 4: Discovery and optimization of a benzylic alcohol series. Bioorg. Med. Chem. Lett., 2011, 21(8), 2207-2211.
[http://dx.doi.org/10.1016/j.bmcl.2011.03.009] [PMID: 21441027]
[89]
Ebert, K.; Wiemer, J.; Caballero, J.; Köckerling, M.; Steinbach, J.; Pietzsch, J.; Mamat, C. Development of indazolylpyrimidine derivatives as high-affine EphB4 receptor ligands and potential PET radiotracers. Bioorg. Med. Chem., 2015, 23(17), 6025-6035.
[http://dx.doi.org/10.1016/j.bmc.2015.06.040] [PMID: 26189032]
[90]
Lafleur, K.; Huang, D.; Zhou, T.; Caflisch, A.; Nevado, C. Structure-based optimization of potent and selective inhibitors of the tyrosine kinase erythropoietin producing human hepatocellular carcinoma receptor B4 (EphB4). J. Med. Chem., 2009, 52(20), 6433-6446.
[http://dx.doi.org/10.1021/jm9009444] [PMID: 19788238]
[91]
Kathawala, R.J.; Wei, L.; Anreddy, N.; Chen, K.; Patel, A.; Alqahtani, S.; Zhang, Y.K.; Wang, Y.J.; Sodani, K.; Kaddoumi, A.; Ashby, C.R., Jr; Chen, Z.S. The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study. Oncotarget, 2015, 6(1), 510-521.
[http://dx.doi.org/10.18632/oncotarget.2638] [PMID: 25402202]
[92]
Ullah, A.; Aziz, T.; Ullah, N.; Nawaz, T. Molecular mechanisms of sanguinarine in cancer prevention and treatment. Anticancer. Agents Med. Chem., 2023, 23(7), 765-778.
[http://dx.doi.org/10.2174/1871520622666220831124321] [PMID: 36045531]
[93]
Yang, M.; Qian, X.H.; Zhao, D.H.; Fu, S.Z. Effects of Astragalus polysaccharide on the erythroid lineage and microarray analysis in K562 cells. J. Ethnopharmacol., 2010, 127(2), 242-250.
[http://dx.doi.org/10.1016/j.jep.2009.11.013] [PMID: 19922785]
[94]
Koolpe, M.; Burgess, R.; Dail, M.; Pasquale, E.B. EphB receptor-binding peptides identified by phage display enable design of an antagonist with ephrin-like affinity. J. Biol. Chem., 2005, 280(17), 17301-17311.
[http://dx.doi.org/10.1074/jbc.M500363200] [PMID: 15722342]
[95]
Kertesz, N.; Krasnoperov, V.; Reddy, R.; Leshanski, L.; Kumar, S.R.; Zozulya, S.; Gill, P.S. The soluble extracellular domain of EphB4 (sEphB4) antagonizes EphB4-EphrinB2 interaction, modulates angiogenesis, and inhibits tumor growth. Blood, 2006, 107(6), 2330-2338.
[http://dx.doi.org/10.1182/blood-2005-04-1655] [PMID: 16322467]
[96]
Martiny-Baron, G.; Korff, T.; Schaffner, F.; Esser, N.; Eggstein, S.; Marmé, D.; Augustin, H.G. Inhibition of tumor growth and angiogenesis by soluble EphB4. Neoplasia, 2004, 6(3), 248-257.
[http://dx.doi.org/10.1593/neo.03457] [PMID: 15153337]
[97]
Noberini, R.; Lamberto, I.; Pasquale, E.B. Targeting Eph receptors with peptides and small molecules: Progress and challenges. Semin. Cell Dev. Biol., 2012, 23(1), 51-57.
[http://dx.doi.org/10.1016/j.semcdb.2011.10.023] [PMID: 22044885]
[98]
Chrencik, J. E.; Brooun, A.; Recht, M. I.; Kraus, M. L.; Koolpe, M.; Kolatkar, A. R.; Bruce, R. H.; Martiny-Baron, G.; Widmer, H.; Pasquale, E. B.; Kuhn, P. Structure and thermodynamic characterization of the EphB4/Ephrin-B2 antagonist peptide complex reveals the determinants for receptor specificity. Structure, 2006, 14(2), 321-30.
[99]
Overman, R.C.; Debreczeni, J.E.; Truman, C.M.; McAlister, M.S.; Attwood, T.K. Completing the structural family portrait of the human EphB tyrosine kinase domains. Protein Sci., 2014, 23(5), 627-638.
[http://dx.doi.org/10.1002/pro.2445] [PMID: 24677421]
[100]
Lee, T.H.; Heo, J.H.; Jeong, J.Y.; Lee, G.H.; Park, D.S.; Kim, T.H. Low expression of EphB2, EphB3, and EphB4 in bladder cancer: Novel potential indicators of muscular invasion. Yonsei Med. J., 2021, 62(8), 679-690.
[http://dx.doi.org/10.3349/ymj.2021.62.8.679] [PMID: 34296545]
[101]
Mincer, S.T.; Niethamer, T.K.; Teng, T.; Bush, J.O.; Percival, C.J. Investigating the effects of compound paralogous EPHB receptor mutations on mouse facial development. Dev. Dyn., 2022, 251(7), 1138-1155.
[http://dx.doi.org/10.1002/dvdy.454] [PMID: 35025117]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy