Recombinant attenuated Salmonella typhimurium carrying a plasmid co-expressing ENDO-VEGI151 and survivin siRNA inhibits the growth of breast cancer in vivo

Li,Zhe; Yin,Pei-Hao; Yang,Sheng-Sheng; Li,Qian-Yu; Chang,Tao; Fang,Lin; Shi,Lin-Xiang; Fang,Guo-En

doi:10.3892/mmr.2013.1308

Recombinant attenuated Salmonella typhimurium carrying a plasmid co-expressing ENDO-VEGI151 and survivin siRNA inhibits the growth of breast cancer in vivo

Authors:
- Zhe Li
- Pei-Hao Yin
- Sheng-Sheng Yang
- Qian-Yu Li
- Tao Chang
- Lin Fang
- Lin-Xiang Shi
- Guo-En Fang
View Affiliations

Affiliations: Department of Thyroid and Breast Surgery, The Shanghai Tenth People's Hospital, Tong Ji University, Shanghai 200072, P.R. China, Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China, Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai 200433, P.R. China , Department of Pathology, The Shanghai Tenth People's Hospital, Tong Ji University, Shanghai 200072, P.R. China, Department of General Surgery of Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China
Published online on: February 5, 2013 https://doi.org/10.3892/mmr.2013.1308
Pages: 1215-1222

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

The aim of this study was to investigate the antitumor effect of a plasmid co-expressing ENDO-VEGI151 and survivin siRNA on breast cancer in nude mice, and to explore the feasibility of attenuated Salmonella typhimurium (S. typhimurium) as a delivery vector for cancer gene therapy in vivo. Three recombinant expression plasmids pENDO‑VEGI151 (pEV), pSurvivin-siRNA (psi-survivin) and co-expressing plasmid pENDO-VEGI151/survivin‑siRNA (pEV/si-survivin), were transferred into the attenuated S. typhimurium strain SL7207, respectively. MDA-MB-231 cells were infected with these recombinants in vitro, and the expression of ENDO-VEGI151 and survivin was detected. In order to detect S. typhimurium distribution and gene delivery efficiency in vivo, the plasmid pEGFP-N1 which encodes green fluorescent protein was transferred into SL7207, and the recombinant known as SL-pEGFP was orally administered to tumor-bearing nude mice. The gene transfer efficiency, distribution and survival time of the SL-pEGFP in vivo were evaluated by detection of GFP fluorescence. SL-pEGFP not only infected the cancer cells effectively, but also allowed the survival and expression of specific genes mainly in the xenografts of nude mice. To further identify the anticancer effects of these recombinants in vivo, mice burdened with xenografts were randomly divided into 6 groups, which were subjected to intragastric administration of vehicle, SL7207, SL-pcDNA3.1, SL-pEV, SL-psi-survivin and SL-pEV/si-survivin, respectively. Eight weeks after implantation, tumor size, weight, inhibition rate, intratumoral microvessel density (MVD), apoptotic index (AI), ENDO‑VEGI151 and survivin expression were evaluated. Compared with the SL-pEV or SL-psi-survivin-treated groups, the growth of tumors was significantly reduced in the SL-pEV/si-survivin group with an inhibition rate of 90.28 vs. 69.12 and 65.61%, respectively. MVD and the expression of survivin were decreased significantly in the SL-pEV/si-survivin-treated group, while AI increased significantly in the SL-pEV/si-survivin-treated group. These results indicated that attenuated S. typhimurium carrying the dual function plasmid pEV/si-survivin cannot only be specifically enriched in the tumor tissue, but also showed a synergistic antitumor effect in vivo.

View Figures

View References

1	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar
2	Grammatikakis I, Zervoudis S and Kassanos D: Synopsis of new antiangiogenetic factors, mutation compensation agents, and monoclonal antibodies in target therapies of breast cancer. J BUON. 15:639–646. 2010.PubMed/NCBI
3	Stoff-Khalili MA, Dall P and Curiel DT: Gene therapy for carcinoma of the breast. Cancer Gene Ther. 13:633–647. 2006. View Article : Google Scholar : PubMed/NCBI
4	Butler JM, Kobayashi H and Rafii S: Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer. 10:138–146. 2010. View Article : Google Scholar : PubMed/NCBI
5	Weigand M, Hantel P, Kreienberg R and Waltenberger J: Autocrine vascular endothelial growth factor signalling in breast cancer. Evidence from cell lines and primary breast cancer cultures in vitro. Angiogenesis. 8:197–204. 2005. View Article : Google Scholar
6	Li Z, Yang S, Chang T, Cao X, Shi L and Fang G: Anti-angiogenesis and anticancer effects of a plasmid expressing both ENDO-VEGI151 and small interfering RNA against survivin. Int J Mol Med. 29:485–490. 2012.PubMed/NCBI
7	Cao S, Cripps A and Wei MQ: New strategies for cancer gene therapy: progress and opportunities. Clin Exp Pharmacol Physiol. 37:108–114. 2010. View Article : Google Scholar : PubMed/NCBI
8	Jimeno A and Hidalgo M: Multitargeted therapy: can promiscuity be praised in an era of political correctness? Crit Rev Oncol Hematol. 59:150–158. 2006. View Article : Google Scholar : PubMed/NCBI
9	Zhang Y, Qu ZH, Cui M, Guo C, Zhang XM, Ma CH and Sun WS: Combined endostatin and TRAIL gene transfer suppresses human hepatocellular carcinoma growth and angiogenesis in nude mice. Cancer Biol Ther. 8:466–473. 2009. View Article : Google Scholar : PubMed/NCBI
10	Yu B, Zhang Y, Zhan Y, Zha X, Wu Y, Zhang X, Dong Q, Kong W and Yu X: Co-expression of herpes simplex virus thymidine kinase and Escherichia coli nitroreductase by an hTERT-driven adenovirus vector in breast cancer cells results in additive anti-tumor effects. Oncol Rep. 26:255–264. 2011.PubMed/NCBI
11	Abdollahi A and Folkman J: Evading tumor evasion: current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resist Updat. 13:16–28. 2010. View Article : Google Scholar : PubMed/NCBI
12	Miles DW, Chan A, Dirix LY, et al: Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 28:3239–3247. 2010. View Article : Google Scholar : PubMed/NCBI
13	Robert NJ, Diéras V, Glaspy J, et al: RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 29:1252–1260. 2011. View Article : Google Scholar
14	Kerbel RS: Issues regarding improving the impact of antiangiogenic drugs for the treatment of breast cancer. Breast. 18(Suppl 3): S41–S47. 2009. View Article : Google Scholar : PubMed/NCBI
15	Leite de Oliveira R, Hamm A and Mazzone M: Growing tumor vessels: more than one way to skin a cat -implications for angiogenesis targeted cancer therapies. Mol Aspects Med. 32:71–87. 2011.PubMed/NCBI
16	Pang RW and Poon RT: Clinical implications of angiogenesis in cancers. Vasc Health Risk Manag. 2:97–108. 2006. View Article : Google Scholar : PubMed/NCBI
17	Eichhorn ME, Kleespies A, Angele MK, Jauch KW and Bruns CJ: Angiogenesis in cancer: molecular mechanisms, clinical impact. Langenbecks Arch Surg. 392:371–379. 2007. View Article : Google Scholar : PubMed/NCBI
18	Carrasco RA, Stamm NB, Marcusson E, Sandusky G, Iversen P and Patel BK: Antisense inhibition of survivin expression as a cancer therapeutic. Mol Cancer Ther. 10:221–232. 2011. View Article : Google Scholar : PubMed/NCBI
19	Rice C and Huang LE: From antiangiogenesis to hypoxia: current research and future directions. Cancer Manag Res. 3:9–16. 2010.PubMed/NCBI
20	Peng XH, Karna P, Cao Z, Jiang BH, Zhou M and Yang L: Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J Biol Chem. 281:25903–25914. 2006. View Article : Google Scholar
21	Liu C, Liang B, Wang Q, Wu J and Zou MH: Activation of AMP-activated protein kinase alpha1 alleviates endothelial cell apoptosis by increasing the expression of anti-apoptotic proteins Bcl-2 and survivin. J Biol Chem. 285:15346–15355. 2010. View Article : Google Scholar : PubMed/NCBI
22	Gardlik R and Fruehauf JH: Bacterial vectors and delivery systems in cancer therapy. IDrugs. 13:701–706. 2010.PubMed/NCBI
23	Gardlik R, Behuliak M, Palffy R, Celec P and Li CJ: Gene therapy for cancer: bacteria-mediated anti-angiogenesis therapy. Gene Ther. 18:425–431. 2011. View Article : Google Scholar : PubMed/NCBI
24	Ji K, Wang B, Shao YT, et al: Synergistic suppression of prostatic cancer cells by coexpression of both murine double minute 2 small interfering RNA and wild-type p53 gene in vitro and in vivo. J Pharmacol Exp Ther. 338:173–183. 2011. View Article : Google Scholar : PubMed/NCBI
25	Zhu X, Zhou P, Cai J, Yang G, Liang S and Ren D: Tumor antigen delivered by Salmonella III secretion protein fused with heat shock protein 70 induces protection and eradication against murine melanoma. Cancer Sci. 101:2621–2628. 2010. View Article : Google Scholar : PubMed/NCBI
26	Lu XL, Jiang XB, Liu RE and Zhang SM: The enhanced anti-angiogenic and antitumor effects of combining flk1-based DNA vaccine and IP-10. Vaccine. 26:5352–5357. 2008. View Article : Google Scholar : PubMed/NCBI