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

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.

• Authors: Xiaoying Feng, Eiman Aleem, Yingbo Lin, Magnus Axelson, Olle Larsson, Thomas Strömberg
• Journal: International journal of oncology (Int J Oncol) Vol. 40 Issue 4 Pg. 1251-8 (Apr 2012) ISSN: 1791-2423 [Electronic] Greece
• PMID: 22159423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• picropodophyllin
• Podophyllotoxin

Topics

• Adenocarcinoma (drug therapy, genetics, metabolism, pathology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Colonic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Down-Regulation (drug effects)
• HCT116 Cells
• HT29 Cells
• Humans
• Phosphorylation
• Podophyllotoxin (analogs & derivatives, pharmacology)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured