The enhanced antitumor effects of biodegradable cationic heparin-polyethyleneimine nanogels delivering HSulf-1 gene combined with cisplatin on ovarian cancer

Liu,Ping; Gou,Maling; Yi,Tao; Qi,Xiaorong; Xie,Chuan; Zhou,Shengtao; Deng,Hongxin; Wei,Yuquan; Zhao,Xia

doi:10.3892/ijo.2012.1558

The enhanced antitumor effects of biodegradable cationic heparin-polyethyleneimine nanogels delivering HSulf-1 gene combined with cisplatin on ovarian cancer

Authors:
- Ping Liu
- Maling Gou
- Tao Yi
- Xiaorong Qi
- Chuan Xie
- Shengtao Zhou
- Hongxin Deng
- Yuquan Wei
- Xia Zhao
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Affiliations: Department of Gynecology and Obstetrics, Key Laboratory of Obstetric and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital; State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu 610041, Sichuan, P.R. China
Published online on: July 18, 2012 https://doi.org/10.3892/ijo.2012.1558
Pages: 1504-1512

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Abstract

HSulf-1 (heparan sulfate 6-O-endosulfatase 1), a commonly downregulated gene in the majority of ovarian cancer cell lines, has been identified to play an important role in regulating tumorigenesis. Our previous studies demonstrated that HSulf-1 could inhibit angiogenesis and tumorigenesis in vivo. The employment of polymeric nanoparticles to deliver functional gene holds much promise as an effective therapeutic strategy against ovarian cancer. To develop more effective therapy, in this study, we investigated the antitumor effect of heparin-polyethyleneimine (HPEI) nanogels delivering HSulf-1 combined with cisplatin (DDP) on ovarian cancer. Expression of HSulf-1 in vitro and in vivo was determined by reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis. A SKOV3 intraperitoneal ovarian carcinomatosis model in nude mice was established to assess the antitumor efficacy. Mice were treated with NS, pEP/HPEI complexes, pHSulf-1/HPEI complexes, DDP or pHSulf-1/HPEI plus DDP, respectively. Intraperitoneal tumors were weighed. Antiangiogenic effect in vivo was evaluated by CD31 immunostaining and alginate-encapsulate tumor cell assay. Detection of the proliferative cells and apoptotic cells in tumor tissues were performed by Ki-67 staining and TUNEL assay. Stable expression of HSulf-1 was detected in the pHSulf-1/HPEI and pHSulf-1/HPEI plus DDP groups. The combination of pHSulf-1/HPEI complexes with DDP exhibited enhanced antitumor activity, compared with the monotherapy of HSulf-1 or DDP alone (P<0.01). the combination therapy exerted significant antitumor activity through enhanced antiangiogenesis, induction of apoptosis and suppression of cell proliferation. Collectively, these observations provide evidence that HPEI nanogels delivering HSulf-1 combined with DDP may have a promising application in the therapy of human ovarian cancer.

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1	Shridhar V, Sen A, Chien J, Staub J, Avula R, Kovats S, Lee J, Lillie J and Smith DI: Identification of underexpressed genes in early- and late-stage primary ovarian tumors by suppression subtraction hybridization. Cancer Res. 62:262–270. 2002.PubMed/NCBI
2	Morimoto-Tomita M, Uchimura K, Werb Z, Hemmerich S and Rosen SD: Cloning and characterization of two extracellular heparin-degrading endosulfatases in mice and humans. J Biol Chem. 277:49175–49185. 2002. View Article : Google Scholar : PubMed/NCBI
3	Ai X, Do AT, Kusche-Gullberg M, Lindahl U, Lu K and Emerson CP Jr: Substrate specificity and domain functions of extracellular heparan sulfate 6-O-endosulfatases, QSulf1 and QSulf2. J Biol Chem. 281:4969–4976. 2006. View Article : Google Scholar : PubMed/NCBI
4	Dhoot GK, Gustafsson MK, Ai X, Sun W, Standiford DM and Emerson CP Jr: Regulation of Wnt signaling and embryo patterning by an extracellular sulfatase. Science. 293:1663–1666. 2001. View Article : Google Scholar : PubMed/NCBI
5	Selva EM and Perrimon N: Role of heparan sulfate proteoglycans in cell signaling and cancer. Adv Cancer Res. 83:67–80. 2001. View Article : Google Scholar : PubMed/NCBI
6	Lin X: Functions of heparan sulfate proteoglycans in cell signaling during development. Development. 131:6009–6021. 2004. View Article : Google Scholar : PubMed/NCBI
7	Lai JP, Chien J, Staub J, Avula R, Greene EL, Matthews TA, Smith DI, Kaufmann SH, Roberts LR and Shridhar V: Loss of HSulf-1 up-regulates heparin-binding growth factor signaling in cancer. J Biol Chem. 278:23107–23117. 2003. View Article : Google Scholar : PubMed/NCBI
8	Lai JP, Chien J, Strome SE, Staub J, Montoya DP, Greene EL, Smith DI, Roberts LR and Shridhar V: HSulf-1 modulates HGF-mediated tumor cell invasion and signaling in head and neck squamous carcinoma. Oncogene. 23:1439–1447. 2004. View Article : Google Scholar : PubMed/NCBI
9	Lai JP, Chien JR, Moser DR, Staub JK, Aderca I, Montoya DP, Matthews TA, Nagorney DM, Cunningham JM, Smith DI, Greene EL, Shridhar V and Roberts LR: hSulf1sulfatase promotes apoptosis of hepatocellular cancer cells by decreasing heparin-binding growth factor signaling. Gastroenterology. 126:231–248. 2004. View Article : Google Scholar : PubMed/NCBI
10	Dai Y, Yang Y, MacLeod V, Yue X, Rapraeger AC, Shriver Z, Venkataraman G, Sasisekharan R and Sanderson RD: HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo. J Biol Chem. 280:40066–40073. 2005. View Article : Google Scholar : PubMed/NCBI
11	Narita K, Staub J, Chien J, Meyer K, Bauer M, Friedl A, Ramakrishnan S and Shridhar V: HSulf-1 inhibits angiogenesis and tumorigenesis in vivo. Cancer Res. 66:6025–6032. 2006. View Article : Google Scholar : PubMed/NCBI
12	Liu P, Khurana A, Rattan R, Kalloger S, Dowdy S, Gilks B and Shridhar V: Regulation of HSulf-1 expression by variant hepatic nuclear factor 1 in ovarian cancer. Cancer Res. 69:4843–4850. 2009. View Article : Google Scholar : PubMed/NCBI
13	Staub J, Chien J, Pan Y, Qian X, Narita K, Aletti G, Roberts LR, Molina J and Shridhar V: Epigenetic silencing of HSulf-1 in ovarian cancer: implications in chemoresistance. Oncogene. 26:4969–4978. 2007. View Article : Google Scholar : PubMed/NCBI
14	Lai JP, Sandhu DS, Shire AM and Roberts LR: The tumor suppressor function of human sulfatase 1 (SULF1) in carcinogenesis. J Gastrointest Cancer. 39:149–158. 2008. View Article : Google Scholar : PubMed/NCBI
15	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar
16	Ozols RF: Progress in ovarian cancer: an overview and perspective. EJC (Suppl). 1:43–55. 2003. View Article : Google Scholar
17	Gonzalez VM, Fuertes MA, Alonso C and Perez JM: Is cisplatin-induced cell death always produced by apoptosis? Mol Pharmacol. 59:657–663. 2001.PubMed/NCBI
18	Fuertes MA, Alonso C and Perez JM: Biochemical modulation of cisplatin mechanisms of action: enhancement of antitumor activity and circumvention of drug resistance. Chem Rev. 103:645–662. 2003. View Article : Google Scholar : PubMed/NCBI
19	Reed E: Platinum-DNA adduct, nucleotide excision repair and platinum based anti-cancer chemotherapy. Cancer Treat Rev. 24:331–344. 1998. View Article : Google Scholar : PubMed/NCBI
20	Cohen SM and Lippard SJ: Cisplatin: from DNA damage to cancer chemotherapy. Prog Nucleic Acid Res Mol Biol. 67:93–130. 2001. View Article : Google Scholar : PubMed/NCBI
21	Edelstein ML, Abedi MR, Wixon J and Edelstein RM: Gene therapy clinical trials worldwide 1989–2004-an overview. J Gene Med. 6:597–602. 2004.
22	Anderson DG, Peng W, Akinc A, Hossain N, Kohn A, Padera R, Langer R and Sawicki JA: A polymer library approach to suicide gene therapy for cancer. Proc Natl Acad Sci USA. 101:16028–16033. 2004. View Article : Google Scholar : PubMed/NCBI
23	Ferber D: Gene therapy. Safer and virus-free? Science. 294:1638–1642. 2001. View Article : Google Scholar : PubMed/NCBI
24	Lv H, Zhang S, Wang B, Cui S and Yan J: Toxicity of cationic lipids and cationic polymers in gene delivery. J Control Release. 114:100–109. 2006. View Article : Google Scholar : PubMed/NCBI
25	Neu M, Fischer D and Kissel T: Recent advances in rational gene transfer vector design based on poly(ethyleneimine) and its derivatives. J Gene Med. 7:992–1009. 2005. View Article : Google Scholar : PubMed/NCBI
26	Kunath K, von Harpe A, Fischer D, Petersen H, Bickel U, Voigt K and Kissel T: Low-molecular-weight polyethyleneimine as a non-viral vector for DNA delivery: comparison of physicochemical properties, transfection efficiency and in vivo distribution with high-molecular-weight polyethyleneimine. J Control Release. 89:113–125. 2003. View Article : Google Scholar
27	Wen Y, Pan S, Luo X, Zhang X, Zhang W and Feng M: A biodegradable low molecular weight polyethyleneimine derivative as low toxicity and efficient gene vector. Bioconjug Chem. 20:322–332. 2009. View Article : Google Scholar : PubMed/NCBI
28	Gosselin MA, Guo W and Lee RJ: Efficient gene transfer using reversibly cross-linked low molecular weight polyethyleneimine. Bioconjug Chem. 12:989–994. 2001. View Article : Google Scholar : PubMed/NCBI
29	Forrest ML, Koerber JT and Pack DW: A degradable polyethyleneimine derivative with low toxicity for highly efficient gene delivery. Bioconjug Chem. 14:934–940. 2003. View Article : Google Scholar : PubMed/NCBI
30	Jeon O, Yang HS, Lee TJ and Kim BS: Heparin-conjugated polyethyleneimine for gene delivery. J Control Release. 132:236–242. 2008. View Article : Google Scholar : PubMed/NCBI
31	Gou ML, Men K, Zhang J, Li YH, Song J, Luo S, Shi HS, Wen YJ, Guo G, Huang MJ, Zhao X, Qian ZY and Wei YQ: Efficient inhibition of C-26 colon carcinoma by VSVMP gene delivered by biodegradable cationic nanogel derived from polyethyleneimine. ACS Nano. 4:5573–5584. 2010. View Article : Google Scholar : PubMed/NCBI
32	Liu P, Gou ML, Yi T, Xie C, Qi XR, Zhou ST, Deng HX, Wei YQ and Zhao X: Efficient inhibition of an intraperitoneal xenograft model of human ovarian cancer by HSulf-1 gene delivered by biodegradable cationic heparin-polyethyleneimine nanogels. Oncol Rep. 27:363–370. 2012.
33	Lin XJ, Chen XC, Wang L, Wei YQ, Kan B, Wen YJ, He X and Zhao X: Dynamic progression of an intraperitoneal xenograft model of human ovarian cancer and its potential for preclinical trials. J Exp Clin Cancer Res. 26:467–474. 2007.PubMed/NCBI
34	Hoffmann J, Schirner M, Menrad A and Schneider MR: A highly sensitive model for quantification of in vivo tumor angiogenesis induced by alginate-encapsulated tumor cells. Cancer Res. 57:3847–3851. 1997.PubMed/NCBI
35	He QM, Wei YQ, Tian L, Zhao X, Su JM, Yang L, Lu Y, Kan B, Lou YY, Huang MJ, Xiao F, Liu JY, Hu B, Luo F, Jiang Y, Wen YJ, Deng HX, Li J, Niu T and Yang JL: Inhibition of tumor growth with a vaccine based on xenogeneic homologous fibroblast growth factor receptor-1 in mice. J Biol Chem. 278:21831–21836. 2003. View Article : Google Scholar : PubMed/NCBI
36	Hu L, Hofmann J, Zaloudek C, Ferrara N, Hamilton T and Jaffe RB: Vascular endothelial growth factor immunoneutralization plus paclitaxel markedly reduces tumor burden and ascites in athymic mouse model of ovarian cancer. Am J Pathol. 161:1917–1924. 2002. View Article : Google Scholar
37	Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 82:4–6. 1990. View Article : Google Scholar : PubMed/NCBI
38	Carmeliet P and Jain RK: Angiogenesis in cancer and other diseases. Nature. 407:249–257. 2000. View Article : Google Scholar : PubMed/NCBI
39	Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P and Kerbel RS: Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest. 105:R15–R24. 2000. View Article : Google Scholar : PubMed/NCBI
40	Neri D and Bicknell R: Tumour vascular targeting. Nat Rev Cancer. 5:436–446. 2005. View Article : Google Scholar