Summary
Integrin αvβ3 plays a critical role in the survival and metastasis process of cancer cells. It is therefore desirable to develop new types of small molecule inhibitors of integrin αvβ3. IH1062 (3, 5-dichloro-phenylbiguanide) is a novel small molecule inhibitor of integrin αvβ3 that we have recently discovered. In this study, we investigated the induction effects of anoikis in human melanoma cell line M21 by IH1062, by detecting caspase activity, measuring the expression levels of apoptosis-related proteins, and performing the AnnexinV/PI apoptosis assay. Furthermore, we established a melanoma pulmonary metastasis mouse model in order to evaluate the suppression of metastasis by IH1062 in vivo. Our results demonstrate that IH1062 triggered human melanoma M21 cells to undergo anoikis by interrupting the attachment of M21 cells to extracellular matrix, reducing the phosphorylation of focal adhesion kinase, decreasing survivin and the ratio of Bcl-2/Bax proteins, and activating caspase cascades in vitro. Additionally, IH1062 showed markedly anti-metastatic effects in the pulmonary metastasis model in vivo, which makes it a promising lead to develop new drugs for anti-metastasis therapies.
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References
Brooks PC, Clark RA, Cheresh DA (1994) Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 264:569–571. doi:10.1126/science.7512751
Jones JI, Prevette T, Gockerman A et al (1996) Ligand occupancy of the alpha-V-beta3 integrin is necessary for smooth muscle cells to migrate in response to insulin-like growth factor. Proc Natl Acad Sci U S A 93:2482–2487. doi:10.1073/pnas.93.6.2482
Petitclerc E, Strömblad S, von Schalscha TL et al (1999) Integrin αvβ3 promotes M21 melanoma growth in human skin by regulating tumor cell survival. Cancer Res 59:2724–2730
Reinmuth N, Liu W, Ahmad SA et al (2003) αvβ3 integrin antagonist S247 decreases colon cancer metastasis and angiogenesis and improves survival in mice. Cancer Res 63:2079–2087
Lössner D, Abou-Ajram C, Benge A et al (2008) Integrin alphavbeta3 mediates upregulation of epidermal growth-factor receptor expression and activity in human ovarian cancer cells. Int J Biochem Cell Biol 40:2746–2761. doi:10.1016/j.biocel.2008.05.014
Zhou Y, Peng H, Ji Q et al (2006) Discovery of small molecule inhibitors of integrin alphavbeta3 through structure-based virtual screening. Bioorg Med Chem Lett 16:5878–5882. doi:10.1016/j.bmcl.2006.08.061
Maubant S, Dizier DS, Boutillon M et al (2006) Blockade of αvβ3 and αvβ5 integrins by RGD mimetics induces anoikis and not integrin-mediated death in human endothelial cells. Blood 108:3035–3044. doi:10.1182/blood-2006-05-023580
Giancotti FG, Ruoslahti E (1999) Integrin signaling. Science 285:1028–1032. doi:10.1126/science.285.5430.1028
Patsenker E, PopovY WM et al (2007) Pharmacological inhibition of the vitronectin receptor abrogates PDGF-BB-induced hepatic stellate cell migration and activation in vitro. J Hepatol 46:878–887. doi:10.1016/j.jhep.2006.11.011
Chatterjee S, Brite KH, Matsumura A (2001) Induction of apoptosis of integrin-expressing human prostate cancer cells by cyclic Arg-Gly-Asp peptides. Clin Cancer Res 7:3006–3011
Gong W, Liu Y, Huang B et al (2008) Recombinant CBD–HepII polypeptide of fibronectin inhibits αvβ3 signaling and hematogenous metastasis of tumor. Biochem Biophys Res Commun 367:144–149. doi:10.1016/j.bbrc.2007.12.110
Zhou XY, Murphy FR, Gehdu N et al (2004) Engagement ofαvβ3 integrin regulates proliferation and apoptosis of hepatic stellate cells. J Biol Chem 279:23996–4006. doi:10.1074/jbc.M311668200
Shin S, Sung BJ, Cho YS et al (2001) An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. Biochemistry 40:1117–1123. doi:10.1021/bi001603q
von Wnuck LK, Keul P, Ferri N et al (2006) Integrin-mediated transcriptional activation of inhibitor of apoptosis proteins protects smooth muscle cells against apoptosis induced by degraded collagen. Circ Res 98:1490–1497. doi:10.1161/01.RES.0000229267.77982.0d
Cao Q, Cai W, Niu G et al (2008) Multimodality Imaging of IL-18-binding protein-Fc therapy of experimental lung metastasis. Clinical cancer research 14:6137–6145. doi:10.1158/1078-0432.CCR-08-0049
Chen Q, Manning CD, Millar H et al (2008) CNTO 95, a fully human anti alphav integrin antibody, inhibits cell signaling, migration, invasion, and spontaneous metastasis of human breast cancer cells. Clin Exp Metastasis 25:139–148. doi:10.1007/s10585-007-9132-4
Zhao Y, Bachelier R, Treilleux I et al (2007) Tumor alphavbeta3 integrin is a therapeutic target for breast cancer bone metastases. Cancer Res 67:5821–5830. doi:10.1158/0008-5472.CAN-06-4499
Acknowledgements
The work was supported by grant from the Tianjin Municipal Basic Research Priorities Program (No. 07JCZDJC04900), grant from the Chinese National Natural Sciences Foundation (No. 30701012), and grant from Ministry of Education of China (No. 20070023093).
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Yongci Zhang and Ming Yang contributed equally to this work.
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Zhang, Y., Yang, M., Ji, Q. et al. Anoikis induction and metastasis suppression by a new integrin αvβ3 inhibitor in human melanoma cell line M21. Invest New Drugs 29, 666–673 (2011). https://doi.org/10.1007/s10637-010-9616-y
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DOI: https://doi.org/10.1007/s10637-010-9616-y