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Published in: Pathology & Oncology Research 2/2011

01-06-2011 | Research

Combined Antitumor Effect of Ad-bFGF-siRNA and Ad-Vpr on the Growth of Xenograft Glioma in Nude Mouse Model

Authors: Biao Zhang, Xuequan Feng, Jinhuan Wang, Xinnu Xu, Na Lin, Hongsheng Liu

Published in: Pathology & Oncology Research | Issue 2/2011

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Abstract

Basic fibroblast growth factor (bFGF) has been demonstrated to correlate with glioma grade and clinical outcome and has established its possible usefulness as a target for glioma therapy. Vpr has been described as an antitumor agent and displays a potent antitumor nature. Here, we try to investigate whether a combined treatment with bFGF-siRNA and Vpr gene would have a enhanced effectiveness on glioma in vitro and in vivo.After treatments with only Ad-bFGF-siRNA, only Ad-Vpr, and a combination of both, we assessed the changes in cell proliferation, cell cycle, and apoptosis in vitro by the methods of MTT, PI and FITC-AnnexinV double staining, respevtively. In addition, we also evaluated the combined effect of bFGF-siRNA and Vpr gene therapy on glioma in vivo using xenograft glioma models in nude mice. Combined Ad-bFGF-siRNA and Ad-Vpr treatment was more better successful in inhibiting cell proliferation in comparison with treatments of either Ad-bFGF-siRNA or Ad-Vpr alone. Treatment of Ad-Vpr alone or a treatment of a combination of Ad-bFGF-siRNA and Ad-Vpr induced the G2/M cell cycle arrest and apoptosis; however, combined treatment was more effective than the Ad-Vpr treatment alone. Although each single treatment can slow the growth of xenograft glioma, the combined treatment with Ad-bFGF-siRNA and Ad-Vpr was better than either the Ad-bFGF-siRNA or Ad-Vpr treatment alone. Our results suggest that the combination therapy with bFGF-siRNA and Vpr gene can achieve a enhanced activity of anti-glioma, supporting the idea that the combination of these two antitumor agents could open new perspectives in glioma therapy.
Literature
1.
go back to reference Hutterer M, Knyazev P, Abate A, Reschke M, Maier H, Stefanova N, Knyazeva T, Barbieri V, Reindl M, Muigg A, Kostron H, Stockhammer G, Ullrich A (2008) Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme. Clin Cancer Res 14(1):130–138PubMedCrossRef Hutterer M, Knyazev P, Abate A, Reschke M, Maier H, Stefanova N, Knyazeva T, Barbieri V, Reindl M, Muigg A, Kostron H, Stockhammer G, Ullrich A (2008) Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme. Clin Cancer Res 14(1):130–138PubMedCrossRef
2.
go back to reference Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996PubMedCrossRef Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996PubMedCrossRef
3.
go back to reference Auguste P, Gursel DB, Lemiere S, Reimers D, Cuevas P, Carceller F, Di Santo JP, Bikfalvi A (2001) Inhibition of fibroblast growth factor/fibroblast growth factor receptor activity in glioma cells impedes tumor growth by both angiogenesis-dependent and -independent mechanisms. Cancer Res 61(4):1717–1726PubMed Auguste P, Gursel DB, Lemiere S, Reimers D, Cuevas P, Carceller F, Di Santo JP, Bikfalvi A (2001) Inhibition of fibroblast growth factor/fibroblast growth factor receptor activity in glioma cells impedes tumor growth by both angiogenesis-dependent and -independent mechanisms. Cancer Res 61(4):1717–1726PubMed
4.
go back to reference Ryther RC, Flynt AS, Phillips JA 3rd, Patton JG (2005) siRNA therapeutics: big potential from small RNAs. Gene Ther 12(1):5–11PubMedCrossRef Ryther RC, Flynt AS, Phillips JA 3rd, Patton JG (2005) siRNA therapeutics: big potential from small RNAs. Gene Ther 12(1):5–11PubMedCrossRef
5.
go back to reference Muthumani K, Hwang DS, Desai BM, Zhang D, Dayes N, Green DR, Weiner DB (2002) HIV-1 Vpr induces apoptosis through caspase 9 in T cells and peripheral blood mononuclear cells. J Biol Chem 277(40):37820–37831PubMedCrossRef Muthumani K, Hwang DS, Desai BM, Zhang D, Dayes N, Green DR, Weiner DB (2002) HIV-1 Vpr induces apoptosis through caspase 9 in T cells and peripheral blood mononuclear cells. J Biol Chem 277(40):37820–37831PubMedCrossRef
6.
go back to reference Muthumani K, Zhang D, Hwang DS, Kudchodkar S, Dayes NS, Desai BM, Malik AS, Yang JS, Chattergoon MA, Maguire HC Jr, Weiner DB (2002) Adenovirus encoding HIV-1 Vpr activates caspase 9 and induces apoptotic cell death in both p53 positive and negative human tumor cell lines. Oncogene 21(30):4613–4625PubMedCrossRef Muthumani K, Zhang D, Hwang DS, Kudchodkar S, Dayes NS, Desai BM, Malik AS, Yang JS, Chattergoon MA, Maguire HC Jr, Weiner DB (2002) Adenovirus encoding HIV-1 Vpr activates caspase 9 and induces apoptotic cell death in both p53 positive and negative human tumor cell lines. Oncogene 21(30):4613–4625PubMedCrossRef
7.
go back to reference McCray AN, Ugen KE, Heller R (2007) Enhancement of anti-melanoma activity of a plasmid expressing HIV-1 Vpr delivered through in vivo electroporation. Cancer Biol Ther 6(8):1269–1275PubMed McCray AN, Ugen KE, Heller R (2007) Enhancement of anti-melanoma activity of a plasmid expressing HIV-1 Vpr delivered through in vivo electroporation. Cancer Biol Ther 6(8):1269–1275PubMed
8.
go back to reference McCray AN, Ugen KE, Muthumani K, Kim JJ, Weiner DB, Heller R (2006) Complete regression of established subcutaneous B16 murine melanoma tumors after delivery of an HIV-1 Vpr-expressing plasmid by in vivo electroporation. Mol Ther 14(5):647–655PubMedCrossRef McCray AN, Ugen KE, Muthumani K, Kim JJ, Weiner DB, Heller R (2006) Complete regression of established subcutaneous B16 murine melanoma tumors after delivery of an HIV-1 Vpr-expressing plasmid by in vivo electroporation. Mol Ther 14(5):647–655PubMedCrossRef
9.
go back to reference Muthumani K, Choo AY, Hwang DS, Ugen KE, Weiner DB (2004) HIV-1 Vpr: enhancing sensitivity of tumors to apoptosis. Curr Drug Deliv 1(4):335–344PubMedCrossRef Muthumani K, Choo AY, Hwang DS, Ugen KE, Weiner DB (2004) HIV-1 Vpr: enhancing sensitivity of tumors to apoptosis. Curr Drug Deliv 1(4):335–344PubMedCrossRef
10.
go back to reference Muthumani K, Lambert VM, Sardesai NY, Kim JJ, Heller R, Weiner DB, Ugen KE (2009) Analysis of the potential for HIV-1 Vpr as an anti-cancer agent. Curr HIV Res 7(2):144–152PubMedCrossRef Muthumani K, Lambert VM, Sardesai NY, Kim JJ, Heller R, Weiner DB, Ugen KE (2009) Analysis of the potential for HIV-1 Vpr as an anti-cancer agent. Curr HIV Res 7(2):144–152PubMedCrossRef
11.
go back to reference Muthumani K, Lambert VM, Shanmugam M, Thieu KP, Choo AY, Chung JC, Satishchandran A, Kim JJ, Weiner DB, Ugen KE (2009) Anti-tumor activity mediated by protein and peptide transduction of HIV viral protein R (Vpr). Cancer Biol Ther 8(2):180–187PubMedCrossRef Muthumani K, Lambert VM, Shanmugam M, Thieu KP, Choo AY, Chung JC, Satishchandran A, Kim JJ, Weiner DB, Ugen KE (2009) Anti-tumor activity mediated by protein and peptide transduction of HIV viral protein R (Vpr). Cancer Biol Ther 8(2):180–187PubMedCrossRef
13.
go back to reference Jordan JP, Hand CM, Markowitz RS, Black P (1992) Test for chemotherapeutic sensitivity of cerebral gliomas: use of colorimetric MTT assay. J Neurooncol 14(1):19–35PubMedCrossRef Jordan JP, Hand CM, Markowitz RS, Black P (1992) Test for chemotherapeutic sensitivity of cerebral gliomas: use of colorimetric MTT assay. J Neurooncol 14(1):19–35PubMedCrossRef
14.
go back to reference Chen B, Timiryasova TM, Andres ML, Kajioka EH, Dutta-Roy R, Gridley DS, Fodor I (2000) Evaluation of combined vaccinia virus-mediated antitumor gene therapy with p53, IL-2, and IL-12 in a glioma model. Cancer Gene Ther 7(11):1437–1447PubMedCrossRef Chen B, Timiryasova TM, Andres ML, Kajioka EH, Dutta-Roy R, Gridley DS, Fodor I (2000) Evaluation of combined vaccinia virus-mediated antitumor gene therapy with p53, IL-2, and IL-12 in a glioma model. Cancer Gene Ther 7(11):1437–1447PubMedCrossRef
15.
go back to reference Fukui S, Nawashiro H, Otani N, Ooigawa H, Nomura N, Yano A, Miyazawa T, Ohnuki A, Tsuzuki N, Katoh H, Ishihara S, Shima K (2003) Nuclear accumulation of basic fibroblast growth factor in human astrocytic tumors. Cancer 97(12):3061–3067PubMedCrossRef Fukui S, Nawashiro H, Otani N, Ooigawa H, Nomura N, Yano A, Miyazawa T, Ohnuki A, Tsuzuki N, Katoh H, Ishihara S, Shima K (2003) Nuclear accumulation of basic fibroblast growth factor in human astrocytic tumors. Cancer 97(12):3061–3067PubMedCrossRef
16.
go back to reference Baguma-Nibasheka M, Li AW, Murphy PR (2007) The fibroblast growth factor-2 antisense gene inhibits nuclear accumulation of FGF-2 and delays cell cycle progression in C6 glioma cells. Mol Cell Endocrinol 267(1–2):127–136PubMedCrossRef Baguma-Nibasheka M, Li AW, Murphy PR (2007) The fibroblast growth factor-2 antisense gene inhibits nuclear accumulation of FGF-2 and delays cell cycle progression in C6 glioma cells. Mol Cell Endocrinol 267(1–2):127–136PubMedCrossRef
17.
go back to reference Aoki T, Kato S, Fox JC, Okamoto K, Sakata K, Morimatsu M, Shigemori M (2002) Inhibition of autocrine fibroblast growth factor signaling by the adenovirus-mediated expression of an antisense transgene or a dominant negative receptor in human glioma cells in vitro. Int J Oncol 21(3):629–636PubMed Aoki T, Kato S, Fox JC, Okamoto K, Sakata K, Morimatsu M, Shigemori M (2002) Inhibition of autocrine fibroblast growth factor signaling by the adenovirus-mediated expression of an antisense transgene or a dominant negative receptor in human glioma cells in vitro. Int J Oncol 21(3):629–636PubMed
18.
go back to reference Takahashi JA, Fukumoto M, Kozai Y, Ito N, Oda Y, Kikuchi H, Hatanaka M (1991) Inhibition of cell growth and tumorigenesis of human glioblastoma cells by a neutralizing antibody against human basic fibroblast growth factor. FEBS Lett 288(1–2):65–71PubMedCrossRef Takahashi JA, Fukumoto M, Kozai Y, Ito N, Oda Y, Kikuchi H, Hatanaka M (1991) Inhibition of cell growth and tumorigenesis of human glioblastoma cells by a neutralizing antibody against human basic fibroblast growth factor. FEBS Lett 288(1–2):65–71PubMedCrossRef
19.
go back to reference Marek L, Ware KE, Fritzsche A, Hercule P, Helton WR, Smith JE, McDermott LA, Coldren CD, Nemenoff RA, Merrick DT, Helfrich BA, Bunn PA Jr, Heasley LE (2009) Fibroblast growth factor (FGF) and FGF receptor-mediated autocrine signaling in non-small-cell lung cancer cells. Mol Pharmacol 75(1):196–207PubMedCrossRef Marek L, Ware KE, Fritzsche A, Hercule P, Helton WR, Smith JE, McDermott LA, Coldren CD, Nemenoff RA, Merrick DT, Helfrich BA, Bunn PA Jr, Heasley LE (2009) Fibroblast growth factor (FGF) and FGF receptor-mediated autocrine signaling in non-small-cell lung cancer cells. Mol Pharmacol 75(1):196–207PubMedCrossRef
20.
go back to reference Wang SJ, Wang JH, Zhang YW, Xu XN, Liu HS (2008) Effects of small interfering RNA targeting basic fibroblast growth factor on proliferation and apoptosis of glioma cell line U251. Ai Zheng 27(9):905–909PubMed Wang SJ, Wang JH, Zhang YW, Xu XN, Liu HS (2008) Effects of small interfering RNA targeting basic fibroblast growth factor on proliferation and apoptosis of glioma cell line U251. Ai Zheng 27(9):905–909PubMed
Metadata
Title
Combined Antitumor Effect of Ad-bFGF-siRNA and Ad-Vpr on the Growth of Xenograft Glioma in Nude Mouse Model
Authors
Biao Zhang
Xuequan Feng
Jinhuan Wang
Xinnu Xu
Na Lin
Hongsheng Liu
Publication date
01-06-2011
Publisher
Springer Netherlands
Published in
Pathology & Oncology Research / Issue 2/2011
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-010-9303-5

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