In vitro and in vivo activities of an antitumor peptide HM-3: A special dose-efficacy relationship on an HCT‑116 xenograft model in nude mice Corrigendum in /10.3892/or.2020.7503

Yassin,Sitelbanat; Hu,Jialiang; Xu,Hanmei; Li,Ce; Setrerrahmane,Sarra

doi:10.3892/or.2016.5077

In vitro and in vivo activities of an antitumor peptide HM-3: A special dose-efficacy relationship on an HCT‑116 xenograft model in nude mice

Corrigendum in: /10.3892/or.2020.7503

Authors:
- Sitelbanat Yassin
- Jialiang Hu
- Hanmei Xu
- Ce Li
- Sarra Setrerrahmane
View Affiliations

Affiliations: The Engineering Research Center of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China
Published online on: September 9, 2016 https://doi.org/10.3892/or.2016.5077
Pages: 2951-2959

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

Anti-angiogenesis is an important therapy for cancer treatment. Peptide HM-3 is an integrin antagonist with anti-angiogenic and antitumor activity. Previous research found that HM-3 at an effective dose inhibited tumor growth whereas at higher doses, the inhibitory effect gradually decreased. In the present study, three human tumor cell lines, human colorectal cancer cell (HCT-116) and human hepatic cancer cell (Hep G-2 and SMMC-7721), were selected and their interactions with HM-3 were compared with western blot and flow cytometric assays. The effect of HM-3 on the migration of two tumor cell lines (HCT-116 and Hep G-2) was also evaluated and a bell-shaped dose-efficacy curve was found for both cell lines. Furthermore, in vivo imaging in BALB/c nude mice confirmed that HM-3 had a short half-life and targeted the tumor tissue. Moreover, on an HCT-116 xenograft model in BALB/c nude mice, HM-3 at 3 mg/kg inhibited tumor growth with an inhibition rate of 71.5% (by tumor mass) whereas at 12 and 48 mg/kg, the inhibition rates were 59.2 and 36.0%, respectively. Immunohistochemistry analyses found that both sunitinib (60 mg/kg) and HM-3 (3 and 48 mg/kg) decreased microvascular density and increased percent of HIF-1α and VEGF expressing cells. The present study investigated the effect of tumor microenvironments on the antitumor effect of HM-3 and concluded that HM-3 inhibited angiogenesis and thereafter tumor growth by directly inhibiting HUVEC migration. The special dose-efficacy curves for antitumor effect and for cell migration inhibition were correlated. The present study also confirmed that the effective dose has to be strictly defined for better clinical applications of anti‑angiogenic drugs such as HM-3.

View Figures

View References

1	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
2	Folkman J: Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med. 333:1757–1763. 1995. View Article : Google Scholar : PubMed/NCBI
3	Sharma RA, Harris AL, Dalgleish AG, Steward WP and O'Byrne KJ: Angiogenesis as a biomarker and target in cancer chemoprevention. Lancet Oncol. 2:726–732. 2001. View Article : Google Scholar
4	Carmeliet P and Jain RK: Angiogenesis in cancer and other diseases. Nature. 407:249–257. 2000. View Article : Google Scholar : PubMed/NCBI
5	Cai W and Chen X: Anti-angiogenic cancer therapy based on integrin alphavbeta3 antagonism. Anticancer Agents Med Chem. 6:407–428. 2006. View Article : Google Scholar : PubMed/NCBI
6	Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, et al: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial. Lancet. 368:1329–1338. 2006. View Article : Google Scholar : PubMed/NCBI
7	Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, et al: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 24:16–24. 2006. View Article : Google Scholar
8	Folkman J: Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 29(Suppl 16): S15–S18. 2002. View Article : Google Scholar
9	Brooks PC, Clark RA and Cheresh DA: Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 264:569–571. 1994. View Article : Google Scholar : PubMed/NCBI
10	Jin H and Varner J: Integrins: Roles in cancer development and as treatment targets. Br J Cancer. 90:561–565. 2004. View Article : Google Scholar : PubMed/NCBI
11	Kumar CC: Integrin alpha v beta 3 as a therapeutic target for blocking tumor-induced angiogenesis. Curr Drug Targets. 4:123–131. 2003. View Article : Google Scholar : PubMed/NCBI
12	Liu Z, Wang F and Chen X: Integrin alpha(v)beta(3)-targeted cancer therapy. Drug Dev Res. 69:329–339. 2008. View Article : Google Scholar : PubMed/NCBI
13	Meerovitch K, Bergeron F, Leblond L, Grouix B, Poirier C, Bubenik M, Chan L, Gourdeau H, Bowlin T and Attardo G: A novel RGD antagonist that targets both alphavbeta3 and alpha-5beta1 induces apoptosis of angiogenic endothelial cells on type I collagen. Vascul Pharmacol. 40:77–89. 2003. View Article : Google Scholar : PubMed/NCBI
14	Zhou K, Zheng X, Xu HM, Zhang J, Chen Y, Xi T and Feng T: Studies of poly(ethylene glycol) modification of HM-3 polypeptides. Bioconjug Chem. 20:932–936. 2009. View Article : Google Scholar : PubMed/NCBI
15	Xu HM, Yin R, Chen L, Siraj S, Huang X, Wang M, Fang H and Wang Y: An RGD-modified endostatin-derived synthetic peptide shows antitumor activity in vivo. Bioconjug Chem. 19:1980–1986. 2008. View Article : Google Scholar : PubMed/NCBI
16	Xu H, Pan L, Ren Y, Yang Y, Huang X and Liu Z: RGD-modified angiogenesis inhibitor HM-3 dose: Dual function during cancer treatment. Bioconjug Chem. 22:1386–1393. 2011. View Article : Google Scholar : PubMed/NCBI
17	Reddy AB, Srivastava SK and Ramana KV: Aldose reductase inhibition prevents lipopolysaccharide-induced glucose uptake and glucose transporter 3 expression in RAW264.7 macrophages. Int J Biochem Cell Biol. 42:1039–1045. 2010. View Article : Google Scholar : PubMed/NCBI
18	Liew K, Yong PV, Lim YM, Navaratnam V and Ho AS: 2-Methoxy-1,4-Naphthoquinone (MNQ) suppresses the invasion and migration of a human metastatic breast cancer cell line (MDA-MB-231). Toxicol In Vitro. 28:335–339. 2014. View Article : Google Scholar
19	Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 227:680–685. 1970. View Article : Google Scholar : PubMed/NCBI
20	Zhao C, Wang X, Zhao Y, Li Z, Lin S, Wei Y and Yang H: A novel xenograft model in zebrafish for high-resolution investigating dynamics of neovascularization in tumors. PLoS One. 6:e217682011. View Article : Google Scholar : PubMed/NCBI
21	Plate KH, Breier G, Millauer B, Ullrich A and Risau W: Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res. 53:5822–5827. 1993.PubMed/NCBI
22	Janouskova H, Ray AM, Noulet F, Lelong-Rebel I, Choulier L, Schaffner F, Lehmann M, Martin S, Teisinger J and Dontenwill M: Activation of p53 pathway by Nutlin-3a inhibits the expression of the therapeutic target α5 integrin in colon cancer cells. Cancer Lett. 336:307–318. 2013. View Article : Google Scholar : PubMed/NCBI
23	Cheong SJ, Lee CM, Kim EM, Uhm TB, Jeong HJ, Kim DW, Lim ST and Sohn MH: Evaluation of the therapeutic efficacy of a VEGFR2-blocking antibody using sodium-iodide symporter molecular imaging in a tumor xenograft model. Nucl Med Biol. 38:93–101. 2011. View Article : Google Scholar : PubMed/NCBI
24	Zhang W, Ran S, Sambade M, Huang X and Thorpe PE: A monoclonal antibody that blocks VEGF binding to VEGFR2 (KDR/Flk-1) inhibits vascular expression of Flk-1 and tumor growth in an orthotopic human breast cancer model. Angiogenesis. 5:35–44. 2002. View Article : Google Scholar
25	Taherian A, Li X, Liu Y and Haas TA: Differences in integrin expression and signaling within human breast cancer cells. BMC Cancer. 11:2932011. View Article : Google Scholar : PubMed/NCBI
26	Senger DR, Perruzzi CA, Streit M, Koteliansky VE, de Fougerolles AR and Detmar M: The alpha(1)beta(1) and alpha(2)beta(1) integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis. Am J Pathol. 160:195–204. 2002. View Article : Google Scholar : PubMed/NCBI
27	Szałek E, Karbownik A, Sobańska K, Płotek W, Grabowski T, Nowak M and Grześkowiak E: The penetration of sunitinib through the blood-brain barrier after the administration of ciprofloxacin. Acta Pol Pharm. 71:691–697. 2014.
28	Zhu B, Xu HM, Zhao L, Huang X and Zhang F: Site-specific modification of anti-angiogenesis peptide HM-3 by polyethylene glycol molecular weight of 20 kDa. J Biochem. 148:341–347. 2010. View Article : Google Scholar : PubMed/NCBI
29	Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Inoue M, Bergers G, Hanahan D and Casanovas O: Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 15:220–231. 2009. View Article : Google Scholar : PubMed/NCBI
30	Loges S, Mazzone M, Hohensinner P and Carmeliet P: Silencing or fueling metastasis with VEGF inhibitors: Antiangiogenesis revisited. Cancer Cell. 15:167–170. 2009. View Article : Google Scholar : PubMed/NCBI
31	Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, Parsons JT and Horwitz AR: Cell migration: Integrating signals from front to back. Science. 302:1704–1709. 2003. View Article : Google Scholar : PubMed/NCBI
32	Mahabeleshwar GH, Feng W, Reddy K, Plow EF and Byzova TV: Mechanisms of integrin-vascular endothelial growth factor receptor cross-activation in angiogenesis. Circ Res. 101:570–580. 2007. View Article : Google Scholar : PubMed/NCBI
33	Mahabeleshwar GH, Feng W, Phillips DR and Byzova TV: Integrin signaling is critical for pathological angiogenesis. J Exp Med. 203:2495–2507. 2006. View Article : Google Scholar : PubMed/NCBI
34	Mahabeleshwar GH, Chen J, Feng W, Somanath PR, Razorenova OV and Byzova TV: Integrin affinity modulation in angiogenesis. Cell Cycle. 7:335–347. 2008. View Article : Google Scholar : PubMed/NCBI
35	Byzova TV, Kim W, Midura RJ and Plow EF: Activation of integrin alpha(V)beta(3) regulates cell adhesion and migration to bone sialoprotein. Exp Cell Res. 254:299–308. 2000. View Article : Google Scholar : PubMed/NCBI
36	Byzova TV, Goldman CK, Pampori N, Thomas KA, Bett A, Shattil SJ and Plow EF: A mechanism for modulation of cellular responses to VEGF: Activation of the integrins. Mol Cell. 6:851–860. 2000.PubMed/NCBI
37	Garrett TA, Van Buul JD and Burridge K: VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2. Exp Cell Res. 313:3285–3297. 2007. View Article : Google Scholar : PubMed/NCBI
38	Wu J, Strawn TL, Luo M, Wang L, Li R, Ren M, Xia J, Zhang Z, Ma W, Luo T, et al: Plasminogen activator inhibitor-1 inhibits angiogenic signaling by uncoupling vascular endothelial growth factor receptor-2-αVβ3 integrin cross talk. Arterioscler Thromb Vasc Biol. 35:111–120. 2015. View Article : Google Scholar