Multiple antitumor effects of picropodophyllin in colon carcinoma cell lines: Clinical implications

Feng,Xiaoying; Aleem,Eiman; Lin,Yingbo; Axelson,Magnus; Larsson,Olle; Strömberg,Thomas

doi:10.3892/ijo.2011.1281

Multiple antitumor effects of picropodophyllin in colon carcinoma cell lines: Clinical implications

Authors:
- Xiaoying Feng
- Eiman Aleem
- Yingbo Lin
- Magnus Axelson
- Olle Larsson
- Thomas Strömberg
View Affiliations

Affiliations: Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, 17176 Stockholm, Sweden, Department of Oncology-Pathology, Karolinska Institutet, CCK R8:04, 171 76 Stockholm, Sweden
Published online on: December 6, 2011 https://doi.org/10.3892/ijo.2011.1281
Pages: 1251-1258

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

Although colorectal cancer can be successfully treated by conventional strategies such as chemo/radiotherapy and surgery, a substantial number of cases, in particular those with liver metastases, remain incurable. Therefore, novel treatment approaches are warranted. The IGF-1R and its ligands, mainly IGF-1 and IGF-2, have been suggested to play pivotal roles in proliferation, survival and migration of adenocarcinoma cells of the colon/rectum. Therefore, interference with IGF-1R-mediated signaling may represent a therapeutic option for this malignancy. In this study, semi-quantitative RT-PCR analyses of 48 paired, colorectal cancer patient samples showed significant overexpression of tumor IGF-1R and IGF-2 mRNA. There was also an overexpression of MMP-7, which was significantly correlated with histopathological parameters. Based on these findings, the effect of the IGF-1R-inhibitory cyclolignan picropodophyllin (PPP) was assessed in the four colon carcinoma cell lines HT-29, HCT-116, DLD-1 and CaCO-2. PPP strongly and dose-dependently inhibited proliferation and migration in all cell lines. However, when exposed to 0.5 µM PPP, only HT-29 showed a net decrease of viable cells as compared with the cell number at the beginning of the experiment, a finding that coincided with decreased expression/phosphorylation of IGF-1R, AKT and ERK. This cell line also exhibited PPP-induced downregulation of MMP-7 and MMP-9. Similar to the DLD-1 and HCT-116 cell lines, HT-29 also showed substantial cell detachment in response to PPP. Although a net reduction of cells by PPP seems to require a synchronized downregulation of IGF-1R, AKT and ERK1/2, part of the antitumor effect may be explained by other, possibly IGF-1R-unrelated mechanism(s). Such a multitude of inhibitory effects of PPP in colon cancer cells together with its low toxicity in vivo makes it a promising drug candidate in the treatment of this disease.

View Figures

View References

1	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar
2	Sandhu MS, Dunger DB and Giovannucci EL: Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer. J Natl Cancer Inst. 94:972–980. 2002. View Article : Google Scholar : PubMed/NCBI
3	Center MM, Jemal A, Smith RA and Ward E: Worldwide variations in colorectal cancer. CA Cancer J Clin. 59:366–378. 2009. View Article : Google Scholar : PubMed/NCBI
4	Ullrich A, Gray A, Tam AW, et al: Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. EMBO J. 5:2503–2512. 1986.
5	Navarro M and Baserga R: Limited redundancy of survival signals from the type 1 insulin-like growth factor receptor. Endocrinology. 142:1073–1081. 2001.PubMed/NCBI
6	Belfiore A, Pandini G, Vella V, Squatrito S and Vigneri R: Insulin/IGF-I hybrid receptors play a major role in IGF-I signaling in thyroid cancer. Biochimie. 81:403–407. 1999. View Article : Google Scholar : PubMed/NCBI
7	All-Ericsson C, Girnita L, Seregard S, Bartolazzi A, Jager MJ and Larsson O: Insulin-like growth factor-1 receptor in uveal melanoma: a predictor for metastatic disease and a potential therapeutic target. Invest Ophthalmol Vis Sci. 43:1–8. 2002.PubMed/NCBI
8	Xie Y, Skytting B, Nilsson G, Brodin B and Larsson O: Expression of insulin-like growth factor-1 receptor in synovial sarcoma: association with an aggressive phenotype. Cancer Res. 59:3588–3591. 1999.PubMed/NCBI
9	Sachdev D and Yee D: Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther. 6:1–12. 2007. View Article : Google Scholar : PubMed/NCBI
10	Girnita A, Girnita L, del Prete F, Bartolazzi A, Larsson O and Axelson M: Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth. Cancer Res. 64:236–242. 2004. View Article : Google Scholar : PubMed/NCBI
11	Stromberg T, Ekman S, Girnita L, et al: IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells. Blood. 107:669–678. 2006. View Article : Google Scholar : PubMed/NCBI
12	Menu E, Jernberg-Wiklund H, Stromberg T, et al: Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model. Blood. 107:655–660. 2006. View Article : Google Scholar : PubMed/NCBI
13	Menu E, Jernberg-Wiklund H, De Raeve H, et al: Targeting the IGF-1R using picropodophyllin in the therapeutical 5T2MM mouse model of multiple myeloma: beneficial effects on tumor growth, angiogenesis, bone disease and survival. Int J Cancer. 121:1857–1861. 2007. View Article : Google Scholar
14	Yin S, Girnita A, Stromberg T, et al: Targeting the insulin-like growth factor-1 receptor by picropodophyllin as a treatment option for glioblastoma. Neurooncology. 12:19–27. 2010.PubMed/NCBI
15	Girnita A, All-Ericsson C, Economou MA, et al: The insulin-like growth factor-I receptor inhibitor picropodophyllin causes tumor regression and attenuates mechanisms involved in invasion of uveal melanoma cells. Clin Cancer Res. 12:1383–1391. 2006. View Article : Google Scholar
16	Ekman S, Frodin JE, Harmenberg J, et al: Clinical phase I study with an Insulin-like growth factor-1 receptor inhibitor: experiences in patients with squamous non-small cell lung carcinoma. Acta Oncol. 50:441–447. 2011. View Article : Google Scholar : PubMed/NCBI
17	Midgley R and Kerr D: Colorectal cancer. Lancet. 353:391–399. 1999. View Article : Google Scholar
18	Reinmuth N, Fan F, Liu W, et al: Impact of insulin-like growth factor receptor-I function on angiogenesis, growth, and metastasis of colon cancer. Lab Invest. 82:1377–1389. 2002. View Article : Google Scholar : PubMed/NCBI
19	Wu Y, Yakar S, Zhao L, Hennighausen L and LeRoith D: Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res. 62:1030–1035. 2002.PubMed/NCBI
20	Sounni NE and Noel A: Membrane type-matrix metalloproteinases and tumor progression. Biochimie. 87:329–342. 2005. View Article : Google Scholar : PubMed/NCBI
21	Newell KJ, Witty JP, Rodgers WH and Matrisian LM: Expression and localization of matrix-degrading metalloproteinases during colorectal tumorigenesis. Mol Carcinog. 10:199–206. 1994. View Article : Google Scholar : PubMed/NCBI
22	Barozzi C, Ravaioli M, D'Errico A, et al: Relevance of biologic markers in colorectal carcinoma: a comparative study of a broad panel. Cancer. 94:647–657. 2002. View Article : Google Scholar : PubMed/NCBI
23	Adachi Y, Yamamoto H, Itoh F, Hinoda Y, Okada Y and Imai K: Contribution of matrilysin (MMP-7) to the metastatic pathway of human colorectal cancers. Gut. 45:252–258. 1999. View Article : Google Scholar : PubMed/NCBI
24	Nielsen BS, Timshel S, Kjeldsen L, et al: 92 kDa type IV collagenase (MMP-9) is expressed in neutrophils and macrophages but not in malignant epithelial cells in human colon cancer. Int J Cancer. 65:57–62. 1996. View Article : Google Scholar : PubMed/NCBI
25	Horiuchi S, Yamamoto H, Min Y, Adachi Y, Itoh F and Imai K: Association of ets-related transcriptional factor E1AF expression with tumour progression and overexpression of MMP-1 and matrilysin in human colorectal cancer. J Pathol. 200:568–576. 2003. View Article : Google Scholar
26	Liang CC, Park AY and Guan JL: In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc. 2:329–333. 2007. View Article : Google Scholar : PubMed/NCBI
27	Buck E and Mulvihill M: Small molecule inhibitors of the IGF-1R/IR axis for the treatment of cancer. Expert Opin Investig Drugs. 20:605–621. 2011. View Article : Google Scholar : PubMed/NCBI
28	Reinmuth N, Liu W, Fan F, et al: Blockade of insulin-like growth factor I receptor function inhibits growth and angiogenesis of colon cancer. Clin Cancer Res. 8:3259–3269. 2002.PubMed/NCBI
29	Hakam A, Yeatman TJ, Lu L, et al: Expression of insulin-like growth factor-1 receptor in human colorectal cancer. Hum Pathol. 30:1128–1133. 1999. View Article : Google Scholar : PubMed/NCBI
30	Weber MM, Fottner C, Liu SB, Jung MC, Engelhardt D and Baretton GB: Overexpression of the insulin-like growth factor I receptor in human colon carcinomas. Cancer. 95:2086–2095. 2002. View Article : Google Scholar : PubMed/NCBI
31	Peters G, Gongoll S, Langner C, et al: IGF-1R, IGF-1 and IGF-2 expression as potential prognostic and predictive markers in colorectal-cancer. Virchows Arch. 443:139–145. 2003. View Article : Google Scholar : PubMed/NCBI
32	Nakamura M, Miyamoto S, Maeda H, et al: Matrix metalloproteinase-7 degrades all insulin-like growth factor binding proteins and facilitates insulin-like growth factor bioavailability. Biochem Biophys Res Commun. 333:1011–1016. 2005. View Article : Google Scholar
33	Baserga R: Targeting the IGF-1 receptor: from rags to riches. Eur J Cancer. 40:2013–2015. 2004. View Article : Google Scholar : PubMed/NCBI
34	Vasilcanu R, Vasilcanu D, Sehat B, et al: Insulin-like growth factor type-I receptor-dependent phosphorylation of extracellular signal-regulated kinase 1/2 but not Akt (protein kinase B) can be induced by picropodophyllin. Mol Pharmacol. 73:930–939. 2008. View Article : Google Scholar
35	Vasilcanu R, Vasilcanu D, Rosengren L, et al: Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and beta-arrestin1. Oncogene. 27:1629–1638. 2008. View Article : Google Scholar : PubMed/NCBI
36	Duan Z, Choy E, Harmon D, et al: Insulin-like growth factor-I receptor tyrosine kinase inhibitor cyclolignan picropodophyllin inhibits proliferation and induces apoptosis in multidrug resistant osteosarcoma cell lines. Mol Cancer Ther. 8:2122–2130. 2009. View Article : Google Scholar