Tyrphostin AG 1296 induces glioblastoma cell apoptosis in vitro and in vivo

Li,Hongwei; Zheng,Junning; Guan,Ruiyun; Zhu,Zifeng; Yuan,Xianhou

doi:10.3892/ol.2015.3781

Tyrphostin AG 1296 induces glioblastoma cell apoptosis in vitro and in vivo

Authors:
- Hongwei Li
- Junning Zheng
- Ruiyun Guan
- Zifeng Zhu
- Xianhou Yuan
View Affiliations

Affiliations: Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, P.R. China, Department of Neurosurgery, The Eight People's Hospital of Shenzhen, Shenzhen, Guangdong 510000, P.R. China
Published online on: October 6, 2015 https://doi.org/10.3892/ol.2015.3781
Pages: 3429-3433
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Glioblastoma is the most common type of malignant human brain tumor. Currently available chemotherapies for glioblastoma focus on targeting tyrosine kinases. However, the existing inhibitors of tyrosine kinases have not produced the therapeutic outcomes that were anticipated. In order to investigate the viability alternative chemotherapeutic agents in this disease, the present study examined the anticancer effects of tyrphostin AG 1296, focusing on its involvement in apoptosis in glioblastoma cells. The study aimed to identify whether tyrphostin AG 1296 affects glioblastoma cell growth by inducing cell apoptosis. To achieve this, cell viability, propidium iodide analysis and cell invasion assay were used to measure cell growth, cell apoptosis and cell migration of human glioblastoma cells. The results showed that tyrphostin AG 1296 treatment reduced cell viability and suppressed migration of human glioblastoma cells. It was also demonstrated that tyrphostin AG 1296 induced cell apoptosis in vitro. Finally, tyrphostin AG 1296 was also shown to significantly inhibit the growth of glioblastoma cells and to increase tumor cell apoptosis in vivo. These findings suggest that tyrphostin AG 1296 induces apoptosis, thereby reducing cell viability and capacity for migration of glioblastoma cells.

View Figures

View References

1	Davis FG, Freels S, Grutsch J, et al: Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: An analysis based on surveillance, epidemiology and end results (SEER) data, 1973–1991. J Neurosurg. 88:1–10. 1998. View Article : Google Scholar : PubMed/NCBI
2	Maher EA, Furnari FB, Bachoo RM, et al: Malignant glioma: Genetics and biology of a grave matter. Genes Dev. 15:1311–1333. 2001. View Article : Google Scholar : PubMed/NCBI
3	Ricard D, Idbaih A, Ducray F, et al: Primary brain tumours in adults. Lancet. 379:1984–1996. 2012. View Article : Google Scholar : PubMed/NCBI
4	Aherne NJ, Benjamin LC, Horsley PJ, et al: Improved outcomes with intensity modulated radiation therapy combined with temozolomide for newly diagnosed glioblastoma multiforme. Neurol Res Int. 2014:9456202014. View Article : Google Scholar : PubMed/NCBI
5	Aizer AA, Ancukiewicz M, Nguyen PL, et al: Underutilization of radiation therapy in patients with glioblastoma: Predictive factors and outcomes. Cancer. 120:238–243. 2014. View Article : Google Scholar : PubMed/NCBI
6	Kanu OO, Hughes B, Di C, et al: Glioblastoma Multiforme Oncogenomics and Signaling Pathways. Clin Med Oncol. 3:39–52. 2009.PubMed/NCBI
7	Krause DS and Van Etten RA: Tyrosine kinases as targets for cancer therapy. N Engl J Med. 353:172–187. 2005. View Article : Google Scholar : PubMed/NCBI
8	Guha A, Dashner K, Black PM, Wagner JA and Stiles CD: Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop. Int J Cancer. 60:168–173. 1995. View Article : Google Scholar : PubMed/NCBI
9	Lokker NA, Sullivan CM, Hollenbach SJ, et al: Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: Evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res. 62:3729–3735. 2002.PubMed/NCBI
10	Nazarenko I, Hede SM, He X, et al: PDGF and PDGF receptors in glioma. Ups J Med Sci. 117:99–112. 2012. View Article : Google Scholar : PubMed/NCBI
11	Capdeville R, Buchdunger E, Zimmermann J and Matter A: Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov. 1:493–502. 2002. View Article : Google Scholar : PubMed/NCBI
12	Guo P, Hu B, Gu W, et al: Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment. Am J Pathol. 162:1083–1093. 2003. View Article : Google Scholar : PubMed/NCBI
13	Heldin CH and Westermark B: Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. 79:1283–1316. 1999.PubMed/NCBI
14	Nistér M, Claesson-Welsh L, Eriksson A, Heldin CH and Westermark B: Differential expression of platelet-derived growth factor receptors in human malignant glioma cell lines. J Biol Chem. 266:16755–16763. 1991.PubMed/NCBI
15	Ostman A and Heldin CH: Involvement of platelet-derived growth factor in disease: Development of specific antagonists. Adv Cancer Res. 80:1–38. 2001. View Article : Google Scholar : PubMed/NCBI
16	Kovalenko M, Rönnstrand L, Heldin CH, et al: Phosphorylation site-specific inhibition of platelet-derived growth factor beta-receptor autophosphorylation by the receptor blocking tyrphostin AG1296. Biochemistry. 36:6260–6269. 1997. View Article : Google Scholar : PubMed/NCBI
17	Kovalenko M, Gazit A, Böhmer A, et al: Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. Cancer Res. 54:6106–6114. 1994.PubMed/NCBI
18	Strutz F, Zeisberg M, Renziehausen A, Raschke B, Becker V, van Kooten C and Müller G: TGF-beta 1 induces proliferation in human renal fibroblasts via induction of basic fibroblast growth factor (FGF-2). Kidney Int. 59:579–592. 2001. View Article : Google Scholar : PubMed/NCBI
19	Levitzki A: Protein tyrosine kinase inhibitors as novel therapeutic agents. Pharmacol Ther. 82:231–239. 1999. View Article : Google Scholar : PubMed/NCBI
20	Krystal GW, Carlson P and Litz J: Induction of apoptosis and inhibition of small cell lung cancer growth by the quinoxaline tyrphostins. Cancer Res. 57:2203–2208. 1997.PubMed/NCBI
21	Minami Y, Yamamoto K, Kiyoi H, Ueda R, Saito H and Naoe T: Different antiapoptotic pathways between wild-type and mutated FLT3: Insights into therapeutic targets in leukemia. Blood. 102:2969–2975. 2003. View Article : Google Scholar : PubMed/NCBI
22	Che HY, Guo HY, Si XW, You QY and Lou WY: Additive effect by combination of Akt inhibitor, MK-2206 and PDGFR inhibitor, tyrphostin AG 1296, in suppressing anaplastic thyroid carcinoma cell viability and motility. Onco Targets Ther. 7:425–432. 2014.PubMed/NCBI
23	Sciaccaluga M, D'Alessandro G, Pagani F, et al: Functional cross talk between CXCR4 and PDGFR on glioblastoma cells is essential for migration. PLoS One. 8:e734262013. View Article : Google Scholar : PubMed/NCBI
24	Watanabe T, Ohtani T, Aihara M and Ishiuchi S: Enhanced antitumor effect of YM872 and AG1296 combination treatment on human glioblastoma xenograft models. J Neurosurg. 118:838–845. 2013. View Article : Google Scholar : PubMed/NCBI
25	Fuller GN: The WHO classification of tumours of the central nervous system, 4th edition. Arch Pathol Lab Med. 132:9062008.PubMed/NCBI
26	Louis DN, Holland EC and Cairncross JG: Glioma classification: A molecular reappraisal. Am J Pathol. 159:779–786. 2001. View Article : Google Scholar : PubMed/NCBI
27	Okada H, Kohanbash G, Zhu X, et al: Immunotherapeutic approaches for glioma. Crit Rev Immunol. 29:1–42. 2009. View Article : Google Scholar : PubMed/NCBI
28	Anton K, Baehring JM and Mayer T: Glioblastoma multiforme: Overview of current treatment and future perspectives. Hematol Oncol Clin North Am. 26:825–853. 2012. View Article : Google Scholar : PubMed/NCBI
29	Carrasco-García E, Saceda M and Martinez-Lacaci I: Role of receptor tyrosine kinases and their ligands in glioblastoma. Cells. 3:199–235. 2014. View Article : Google Scholar : PubMed/NCBI
30	Taylor TE, Furnari FB and Cavenee WK: Targeting EGFR for treatment of glioblastoma: Molecular basis to overcome resistance. Curr Cancer Drug Targets. 12:197–209. 2012. View Article : Google Scholar : PubMed/NCBI
31	Vivanco I, Robins HI, Rohle D, Nghiemphu PL, Kubek S, Oldrini B, Chheda MG, Yannuzzi N, et al: Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov. 2:458–471. 2012. View Article : Google Scholar : PubMed/NCBI
32	Johnson JR, Bross P, Cohen M, et al: Approval summary: Imatinib mesylate capsules for treatment of adult patients with newly diagnosed philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Clin Cancer Res. 9:1972–1979. 2003.PubMed/NCBI
33	Cohen MH, Williams G, Johnson JR, et al: Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res. 8:935–942. 2002.PubMed/NCBI
34	Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al: Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 344:1052–1056. 2001. View Article : Google Scholar : PubMed/NCBI
35	Wen PY, Yung WK, Lamborn KR, et al: Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American brain tumor consortium study 99-08. Clin Cancer Res. 12:4899–4907. 2006. View Article : Google Scholar : PubMed/NCBI
36	Rubin BP and Duensing A: Mechanisms of resistance to small molecule kinase inhibition in the treatment of solid tumors. Lab Invest. 86:981–986. 2006. View Article : Google Scholar : PubMed/NCBI
37	Ma Y, Zeng S, Metcalfe DD, et al: The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood. 99:1741–1744. 2002. View Article : Google Scholar : PubMed/NCBI