Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Newly Synthesized Benzimidazoles Inhibit Vascular Endothelial Growth Factor and Matrix Metalloproteinase-2 and -9 Levels in Prostate Cancer Cells

Author(s): Suleyman Ilhan*, Gamze Dilekci, Adem Guner and Hakan Bektas

Volume 22, Issue 11, 2022

Published on: 11 January, 2022

Page: [2109 - 2115] Pages: 7

DOI: 10.2174/1871520621666210924114856

Price: $65

Abstract

Background: Investigating the effects of newly synthesized agents on various molecular mechanisms to understand their mechanism of action is an important step of pre-clinical screening. Benzimidazoles are composed of a unique fused benzene and imidazole ring and have attracted great attention due to their broad bioactivities, including antitumor.

Objective: In the current study, we reported the synthesis of novel benzimidazole derivatives and investigated the possible cytotoxic and anti-angiogenic effects on human prostate cancer and umbilical vein endothelial cells (HUVECs).

Methods: MTT assay was used to assess cell viability. A scratch assay was conducted to monitor the migration of cells. mRNA expression levels of VEGF, MMP-2, and MMP-9 were evaluated using qPCR. Changes in protein levels were evaluated by western blotting.

Results: Compound G1, having a chlorine moiety, showed a potent cytotoxic activity on both prostate cancer cells and HUVECs, and inhibited cell migration via decreasing the mRNA and protein levels of key angiogenesis-related molecules such as VEGF, MMP-2, and MMP-9.

Conclusion: These results suggest that newly synthesized G1 may be a novel anti-angiogenic agent for prostate cancer treatment.

Keywords: Benzimidazole, angiogenesis, VEGF, MMP-2, MMP-9, prostate cancer.

« Previous Next »
Graphical Abstract

[1]
Teo, M.Y.; Rathkopf, D.E.; Kantoff, P. Treatment of advanced prostate cancer. Annu. Rev. Med., 2019, 70, 479-499.
[http://dx.doi.org/10.1146/annurev-med-051517-011947] [PMID: 30691365]
[2]
Shelley, M.D.; Mason, M.D. Metastatic prostate cancer. Evidence-Based Urology; Wiley-blackwell: Oxford, UK, 2010, pp. 293-303.
[http://dx.doi.org/10.1002/9781444323146.ch30]
[3]
Melegh, Z.; Oltean, S. Targeting angiogenesis in prostate cancer. Int. J. Mol. Sci., 2019, 20(11)E2676 Epub ahead of print
[http://dx.doi.org/10.3390/ijms20112676] [PMID: 31151317]
[4]
Viallard, C.; Larrivée, B. Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis, 2017, 20(4), 409-426. Epub ahead of print
[http://dx.doi.org/10.1007/s10456-017-9562-9] [PMID: 28660302]
[5]
Russo, G.; Mischi, M.; Scheepens, W.; De la Rosette, J.J.; Wijkstra, H. Angiogenesis in prostate cancer: onset, progression and imaging. BJU Int., 2012, 110(11 Pt C), E794-E808. Epub ahead of print
[http://dx.doi.org/10.1111/j.1464-410X.2012.11444.x] [PMID: 22958524]
[6]
Quintero-Fabián, S.; Arreola, R.; Becerril-Villanueva, E.; Torres-Romero, J.C.; Arana-Argáez, V.; Lara-Riegos, J.; Ramírez-Camacho, M.A.; Alvarez-Sánchez, M.E. Role of matrix metalloproteinases in angiogenesis and cancer. Front. Oncol., 2019, 9, 1370. Epub ahead of print
[http://dx.doi.org/10.3389/fonc.2019.01370] [PMID: 31921634]
[7]
Carmeliet, P. VEGF as a key mediator of angiogenesis in cancer. Oncology, 2005, 69(Suppl. 3), 4-10. Epub ahead of print
[http://dx.doi.org/10.1159/000088478] [PMID: 16301830]
[8]
Aragon-Ching, J.B.; Dahut, W.L. VEGF inhibitors and prostate cancer therapy. Curr. Mol. Pharmacol., 2009, 2(2), 161-168.
[http://dx.doi.org/10.2174/1874467210902020161] [PMID: 19617926]
[9]
Lin, J.; Kelly, W.K. Targeting angiogenesis as a promising modality for the treatment of prostate cancer. Urol. Clin. North Am., 2012, 39(4), 547-560.
[http://dx.doi.org/10.1016/j.ucl.2012.07.010] [PMID: 23084530]
[10]
Aalinkeel, R.; Nair, M.P.N.; Sufrin, G.; Mahajan, S.D.; Chadha, K.C.; Chawda, R.P.; Schwartz, S.A. Gene expression of angiogenic factors correlates with metastatic potential of prostate cancer cells. Cancer Res., 2004, 64(15), 5311-5321. Epub ahead of print
[http://dx.doi.org/10.1158/0008-5472.CAN-2506-2] [PMID: 15289337]
[11]
Ciombor, K.K.; Bekaii-Saab, T. Selumetinib for the treatment of cancer. Expert Opin. Investig. Drugs, 2015, 24(1), 111-123. Epub ahead of print
[http://dx.doi.org/10.1517/13543784.2015.982275] [PMID: 25385055]
[12]
Atmaca, H.; İlhan, S.; Batır, M.B.; Pulat, Ç.Ç.; Güner, A.; Bektaş, H. Novel benzimidazole derivatives: Synthesis, in vitro cytotoxicity, apoptosis and cell cycle studies. Chem. Biol. Interact., 2020, •••327109163
[http://dx.doi.org/10.1016/j.cbi.2020.109163] [PMID: 32534988]
[13]
Liang, C.C.; Park, A.Y.; Guan, J.L. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat. Protoc., 2007, 2(2), 329-333. Epub ahead of print
[http://dx.doi.org/10.1038/nprot.2007.30] [PMID: 17406593]
[14]
Atmaca, H.; Gorumlu, G.; Karaca, B.; Degirmenci, M.; Tunali, D.; Cirak, Y.; Purcu, D.U.; Uzunoglu, S.; Karabulut, B.; Sanli, U.A.; Uslu, R. Combined gossypol and zoledronic acid treatment results in synergistic induction of cell death and regulates angiogenic molecules in ovarian cancer cells. Eur. Cytokine Netw., 2009, 20(3), 121-130.
[http://dx.doi.org/10.1684/ecn.2009.0159] [PMID: 19825521]
[15]
Karabulut, B.; Karaca, B.; Atmaca, H.; Kisim, A.; Uzunoglu, S.; Sezgin, C.; Uslu, R. Regulation of apoptosis-related molecules by synergistic combination of all-trans retinoic acid and zoledronic acid in hormone-refractory prostate cancer cell lines. Mol. Biol. Rep., 2011, 38(1), 249-259.
[http://dx.doi.org/10.1007/s11033-010-0102-6] [PMID: 20349282]
[16]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin., 2019, 69(1), 7-34.
[http://dx.doi.org/10.3322/caac.21551] [PMID: 30620402]
[17]
Kaliraj, S.; Kathiravan, M.K. Synthesis and cytotoxic evaluation of novel benzimidazole fused condensed thienopyrimdines derivatives. Curr. Bioact. Compd., 2018. Epub ahead of print
[http://dx.doi.org/10.2174/1573407214666180808124802]
[18]
Yurttas, L.; Demirayak, S.; Ciftci, G.A. Cytotoxic, antiproliferative and apoptotic effects of new benzimidazole derivatives on A549 lung carcinoma and C6 glioma cell lines. Anticancer. Agents Med. Chem., 2015, 15(9), 1174-1184.
[http://dx.doi.org/10.2174/1871520615666150703122625] [PMID: 26138412]
[19]
Chen, Q.; Li, Y.; Zhou, X.; Li, R. Oxibendazole inhibits prostate cancer cell growth. Oncol. Lett., 2018, 15(2), 2218-2226.
[PMID: 29434928]
[20]
Lv, P.C.; Li, H.Q.; Sun, J. Synthesis and biological evaluation of pyrazole derivatives containing thiourea skeleton as anticancer agents. Bioorg. Med. Chem., 2010, 18(13), 4604-4614.
[http://dx.doi.org/10.1016/j.bmc.2010.05.034]
[21]
Rashid, M.; Husain, A.; Mishra, R. Design and synthesis of benzimidazoles containing substituted oxadiazole, thiadiazole and triazolo-thiadiazines as a source of new anticancer agents. Arab. J. Chem., 2019. Epub ahead of print
[http://dx.doi.org/10.1016/j.arabjc.2015.08.019]
[22]
Güner, A.; Polatli, E.; Akkan, T. Anticancer and antiangiogenesis activities of novel synthesized 2-substitutedbenzimidazoles molecules. Turk. J. Chem., 2019, 43, 1270-1289.
[23]
Vasaitis, T.; Belosay, A.; Schayowitz, A.; Khandelwal, A.; Chopra, P.; Gediya, L.K.; Guo, Z.; Fang, H.B.; Njar, V.C.; Brodie, A.M. Androgen receptor inactivation contributes to antitumor efficacy of 17α-hydroxylase/17,20-lyase inhibitor 3β-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer. Mol. Cancer Ther., 2008, 7(8), 2348-2357. Epub ahead of print
[http://dx.doi.org/10.1158/1535-7163.MCT-08-0230] [PMID: 18723482]
[24]
Chen, Q.; Li, Y.; Zhou, X. Oxibendazole inhibits prostate cancer cell growth. Oncol. Lett., 2017, 11. Epub ahead of print
[http://dx.doi.org/10.3892/ol.2017.7579] [PMID: 29434928]
[25]
Cheong, J.E.; Zaffagni, M.; Chung, I.; Xu, Y.; Wang, Y.; Jernigan, F.E.; Zetter, B.R.; Sun, L. Synthesis and anticancer activity of novel water soluble benzimidazole carbamates. Eur. J. Med. Chem., 2018, 144, 372-385.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.037] [PMID: 29288939]
[26]
Yuan, X.; Yang, Q.; Liu, T.; Li, K.; Liu, Y.; Zhu, C.; Zhang, Z.; Li, L.; Zhang, C.; Xie, M.; Lin, J.; Zhang, J.; Jin, Y. Design, synthesis and in vitro evaluation of 6-amide-2-aryl benzoxazole/benzimidazole derivatives against tumor cells by inhibiting VEGFR-2 kinase. Eur. J. Med. Chem., 2019, 179, 147-165. Epub ahead of print
[http://dx.doi.org/10.1016/j.ejmech.2019.06.054] [PMID: 31252306]
[27]
Rida, S.M.; Youssef, A.M.; Badr, M.H.; Malki, A.; Sherif, Z.A.; Sultan, A.S. Design, synthesis and evaluation of novel benzimidazoles, benzothiazoles and benzofurans incorporating pyrazole moiety as antiangiogenic agents. Arzneimittelforschung, 2012, 62(2), 63-74. Epub ahead of print
[http://dx.doi.org/10.1055/s-0031-1295483] [PMID: 22344550]
[28]
Lin, K.T.; Lien, J.C.; Chung, C.H.; Kuo, S.C.; Huang, T.F. A novel compound, NP-184, inhibits the vascular endothelial growth factor induced angiogenesis. Eur. J. Pharmacol., 2010, 630(1-3), 53-60. Epub ahead of print
[http://dx.doi.org/10.1016/j.ejphar.2009.12.036] [PMID: 20067787]
[29]
Naumann, K. How chlorine in molecules affects biological activity. Euro Chlor, 2003, 1-37.
[30]
Saman, H.; Raza, S.S.; Uddin, S.; Rasul, K. Inducing angiogenesis, a key step in cancer vascularization, and treatment approaches. Cancers (Basel), 2020, 12(5)E1172 Epub ahead of print
[http://dx.doi.org/10.3390/cancers12051172] [PMID: 32384792]
[31]
Yanagisawa, H.; Amemiya, Y.; Kanazaki, T.; Shimoji, Y.; Fujimoto, K.; Kitahara, Y.; Sada, T.; Mizuno, M.; Ikeda, M.; Miyamoto, S.; Furukawa, Y.; Koike, H. Nonpeptide angiotensin II receptor antagonists: synthesis, biological activities, and structure-activity relationships of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds. J. Med. Chem., 1996, 39(1), 323-338.
[http://dx.doi.org/10.1021/jm950450f] [PMID: 8568823]

Rights & Permissions Print Cite
Article Metrics
34
1
© 2024 Bentham Science Publishers | Privacy Policy