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Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

VS-5584 Inhibits Human Osteosarcoma Cells Growth by Induction of G1- phase Arrest through Regulating PI3K/mTOR and MAPK Pathways

Author(s): Jing-Yi Sun, Ya-Jun Hou, Hai-Juan Cui, Cheng Zhang, Ming-Feng Yang, Feng-Ze Wang, Zheng Sun, Cun-Dong Fan*, Bao-Liang Sun* and Jin Rok Oh*

Volume 20, Issue 8, 2020

Page: [616 - 623] Pages: 8

DOI: 10.2174/1568009620666200414150353

Price: $65

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Abstract

Background: Activation of the PI3K/mTOR signaling pathway plays a key role in the progression of human osteosarcoma. Studies have confirmed that VS-5584 was a novel inhibitor of the PI3K/mTOR pathway, and displayed potential anticancer activity.

Objective: To explore the anticancer effect and underlying mechanism of VS-5584 against the growth of human osteosarcoma cells.

Methods: U2OS and MG-63 human osteosarcoma cells were cultured and the cytotoxicity, cell apoptosis in VS-5584-treated cells were explored by the CCK8 assay, flow cytometric analysis and western blot. Cell migration and tube formation were also employed to examine the anticancer potential.

Results: The results showed that VS-5584 treatment dose-dependently inhibited the growth of U2OS and MG-63 cells by induction of G1-phase arrest through regulating p21, p27, Cyclin B1 and Cdc2. Further investigation revealed that VS-5584 treatment effectively inhibited the PI3K/mTOR signaling pathway and triggered MAPK phosphorylation. Moreover, VS-5584 treatment dramatically suppressed cell migration and tube formation of HUVECs, followed by the down-regulation of HIF-1α and VEGF.

Conclusion: Our findings validated that VS-5584 may be a promising anticancer agent with potential application in the chemotherapy and chemoprevention of human osteosarcoma.

Keywords: VS-5584, osteosarcoma, G1-phase arrest, PI3K/mTOR, MAPK, cytotoxicity.

Graphical Abstract
[1]
Geller, D.S.; Gorlick, R. Osteosarcoma: A review of diagnosis, management, and treatment strategies. Clin. Adv. Hematol. Oncol., 2010, 8(10), 705-718.
[PMID: 21317869]
[2]
Stiller, C.A.; Bielack, S.S.; Jundt, G.; Steliarova-Foucher, E. Bone tumours in European children and adolescents, 1978-1997. Report from the Automated Childhood Cancer Information System project. Eur. J. Cancer, 2006, 42(13), 2124-2135.
[http://dx.doi.org/10.1016/j.ejca.2006.05.015] [PMID: 16919776]
[3]
Khanna, C.; Fan, T.M.; Gorlick, R.; Helman, L.J.; Kleinerman, E.S.; Adamson, P.C.; Houghton, P.J.; Tap, W.D.; Welch, D.R.; Steeg, P.S.; Merlino, G.; Sorensen, P.H.; Meltzer, P.; Kirsch, D.G.; Janeway, K.A.; Weigel, B.; Randall, L.; Withrow, S.J.; Paoloni, M.; Kaplan, R.; Teicher, B.A.; Seibel, N.L.; Smith, M.; Uren, A.; Patel, S.R.; Trent, J.; Savage, S.A.; Mirabello, L.; Reinke, D.; Barkaukas, D.A.; Krailo, M.; Bernstein, M. Toward a drug development path that targets metastatic progression in osteosarcoma. Clin. Cancer Res., 2014, 20(16), 4200-4209.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-2574] [PMID: 24803583]
[4]
McQueen, P.; Ghaffar, S.; Guo, Y.; Rubin, E.M.; Zi, X.; Hoang, B.H. The Wnt signaling pathway: implications for therapy in osteosarcoma. Expert Rev. Anticancer Ther., 2011, 11(8), 1223-1232.
[http://dx.doi.org/10.1586/era.11.94] [PMID: 21916576]
[5]
Siegel, H.J.; Pressey, J.G. Current concepts on the surgical and medical management of osteosarcoma. Expert Rev. Anticancer Ther., 2008, 8(8), 1257-1269.
[http://dx.doi.org/10.1586/14737140.8.8.1257] [PMID: 18699764]
[6]
Osasan, S.; Zhang, M.; Shen, F.; Paul, P.J.; Persad, S.; Sergi, C. Osteogenic sarcoma: A 21st century review. Anticancer Res., 2016, 36(9), 4391-4398.
[http://dx.doi.org/10.21873/anticanres.10982] [PMID: 27630274]
[7]
Ching, C.B.; Hansel, D.E. Expanding therapeutic targets in bladder cancer: The PI3K/Akt/mTOR pathway. Lab. Invest., 2010, 90(10), 1406-1414.
[http://dx.doi.org/10.1038/labinvest.2010.133] [PMID: 20661228]
[8]
Keremu, A.; Maimaiti, X.; Aimaiti, A.; Yushan, M.; Alike, Y.; Yilihamu, Y.; Yusufu, A. NRSN2 promotes osteosarcoma cell proliferation and growth through PI3K/Akt/MTOR and Wnt/β-catenin signaling. Am. J. Cancer Res., 2017, 7(3), 565-573.
[PMID: 28401012]
[9]
Zhang, J.; Yu, X.H.; Yan, Y.G.; Wang, C.; Wang, W.J. PI3K/Akt signaling in osteosarcoma. Clin. Chim. Acta, 2015, 444, 182-192.
[http://dx.doi.org/10.1016/j.cca.2014.12.041] [PMID: 25704303]
[10]
Yuan, T.L.; Cantley, L.C. PI3K pathway alterations in cancer: variations on a theme. Oncogene, 2008, 27(41), 5497-5510.
[http://dx.doi.org/10.1038/onc.2008.245] [PMID: 18794884]
[11]
Hart, S.; Novotny-Diermayr, V.; Goh, K.C.; Williams, M.; Tan, Y.C.; Ong, L.C.; Cheong, A.; Ng, B.K.; Amalini, C.; Madan, B.; Nagaraj, H.; Jayaraman, R.; Pasha, K.M.; Ethirajulu, K.; Chng, W.J.; Mustafa, N.; Goh, B.C.; Benes, C.; McDermott, U.; Garnett, M.; Dymock, B.; Wood, J.M. VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer. Mol. Cancer Ther., 2013, 12(2), 151-161.
[http://dx.doi.org/10.1158/1535-7163.MCT-12-0466] [PMID: 23270925]
[12]
Kolev, V.N.; Wright, Q.G.; Vidal, C.M.; Ring, J.E.; Shapiro, I.M.; Ricono, J.; Weaver, D.T.; Padval, M.V.; Pachter, J.A.; Xu, Q. PI3K/mTOR dual inhibitor VS-5584 preferentially targets cancer stem cells. Cancer Res., 2015, 75(2), 446-455.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-1223] [PMID: 25432176]
[13]
Ning, C.; Liang, M.; Liu, S.; Wang, G.; Edwards, H.; Xia, Y.; Polin, L.; Dyson, G.; Taub, J.W.; Mohammad, R.M.; Azmi, A.S.; Zhao, L.; Ge, Y. Targeting ERK enhances the cytotoxic effect of the novel PI3K and mTOR dual inhibitor VS-5584 in preclinical models of pancreatic cancer. Oncotarget, 2017, 8(27), 44295-44311.
[http://dx.doi.org/10.18632/oncotarget.17869] [PMID: 28574828]
[14]
Weis, S.M.; Cheresh, D.A. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat. Med., 2011, 17(11), 1359-1370.
[http://dx.doi.org/10.1038/nm.2537] [PMID: 22064426]
[15]
Watnick, R.S. The role of the tumor microenvironment in regulating angiogenesis. Cold Spring Harb. Perspect. Med., 2012, 2(12)a006676
[http://dx.doi.org/10.1101/cshperspect.a006676] [PMID: 23209177]
[16]
Xie, L.; Ji, T.; Guo, W. Anti-angiogenesis target therapy for advanced osteosarcoma. (Review) Oncol. Rep., 2017, 38(2), 625-636.
[http://dx.doi.org/10.3892/or.2017.5735] [PMID: 28656259]
[17]
Zhang, J.; Wang, F.; Wang, H.; Wang, Y.; Wu, Y.; Xu, H.; Su, C. Paeoniflorin inhibits proliferation of endometrial cancer cells via activating MAPK and NF-κB signaling pathways. Exp. Ther. Med., 2017, 14(6), 5445-5451.
[http://dx.doi.org/10.3892/etm.2017.5250] [PMID: 29285074]
[18]
Morrison, D.K. MAP kinase pathways. Cold Spring Harb. Perspect. Biol., 2012, 4(11)a011254
[http://dx.doi.org/10.1101/cshperspect.a011254] [PMID: 23125017]
[19]
Sullivan, R.J.; Flaherty, K. MAP kinase signaling and inhibition in melanoma. Oncogene, 2013, 32(19), 2373-2379.
[http://dx.doi.org/10.1038/onc.2012.345] [PMID: 22945644]
[20]
Wang, Z.; Dabrosin, C.; Yin, X.; Fuster, M.M.; Arreola, A.; Rathmell, W.K.; Generali, D.; Nagaraju, G.P.; El-Rayes, B.; Ribatti, D.; Chen, Y.C.; Honoki, K.; Fujii, H.; Georgakilas, A.G.; Nowsheen, S.; Amedei, A.; Niccolai, E.; Amin, A.; Ashraf, S.S.; Helferich, B.; Yang, X.; Guha, G.; Bhakta, D.; Ciriolo, M.R.; Aquilano, K.; Chen, S.; Halicka, D.; Mohammed, S.I.; Azmi, A.S.; Bilsland, A.; Keith, W.N.; Jensen, L.D. Broad targeting of angiogenesis for cancer prevention and therapy. Semin. Cancer Biol., 2015, 35(Suppl.), S224-S243.
[http://dx.doi.org/10.1016/j.semcancer.2015.01.001] [PMID: 25600295]
[21]
Ronca, R.; Benkheil, M.; Mitola, S.; Struyf, S.; Liekens, S. Tumor angiogenesis revisited: Regulators and clinical implications. Med. Res. Rev., 2017, 37(6), 1231-1274.
[http://dx.doi.org/10.1002/med.21452] [PMID: 28643862]
[22]
Kim, M.H.; Jeong, Y.J.; Cho, H.J.; Hoe, H.S.; Park, K.K.; Park, Y.Y.; Choi, Y.H.; Kim, C.H.; Chang, H.W.; Park, Y.J.; Chung, I.K.; Chang, Y.C. Delphinidin inhibits angiogenesis through the suppression of HIF-1α and VEGF expression in A549 lung cancer cells. Oncol. Rep., 2017, 37(2), 777-784.
[http://dx.doi.org/10.3892/or.2016.5296] [PMID: 27959445]
[23]
Hosseini, H.; Rajabibazl, M.; Ebrahimizadeh, W.; Dehbidi, G.R. Inhibiting angiogenesis with human single-chain variable fragment antibody targeting VEGF. Microvasc. Res., 2015, 97, 13-18.
[http://dx.doi.org/10.1016/j.mvr.2014.09.002] [PMID: 25250517]
[24]
Jeong, J.H.; Jeong, Y.J.; Cho, H.J. Ascochlorin inhibits growth factor-induced HIF- 1α activation and tumor-angiogenesis through the suppression of EGFR/ERK/p70S-6K signaling pathway in human cervical carcinoma cells. J. Cell. Biochem., 2012, 113(4), 1302-1313.
[http://dx.doi.org/10.1002/jcb.24001] [PMID: 22109717]
[25]
Ferrara, N.; Gerber, H.P.; LeCouter, J. The biology of VEGF and its receptors. Nat. Med., 2003, 9(6), 669-676.
[http://dx.doi.org/10.1038/nm0603-669] [PMID: 12778165]
[26]
Zeng, Z.; Huang, W.D.; Gao, Q.; Su, M.L.; Yang, Y.F.; Liu, Z.C.; Zhu, B.H. Arnebin-1 promotes angiogenesis by inducing eNOS, VEGF and HIF-1α expression through the PI3K-dependent pathway. Int. J. Mol. Med., 2015, 36(3), 685-697.
[http://dx.doi.org/10.3892/ijmm.2015.2292] [PMID: 26202335]
[27]
Zhang, W.; Ding, X.; Cheng, H.; Yin, C.; Yan, J.; Mou, Z.; Wang, W.; Cui, D.; Fan, C.; Sun, D. Dual-targeted gold nanoprism for recognition of early apoptosis, dual-model imaging and precise cancer photothermal therapy. Theranostics, 2019, 9(19), 5610-5625.
[http://dx.doi.org/10.7150/thno.34755] [PMID: 31534506]

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