title: 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.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Cancer                     Center Karolinska, 17176 Stockholm, Sweden.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Feng
authors.forename: Eiman
authors.initials: E
authors.lastname: Aleem
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Lin
authors.forename: Magnus
authors.initials: M
authors.lastname: Axelson
authors.forename: Olle
authors.initials: O
authors.lastname: Larsson
authors.forename: Thomas
authors.initials: T
authors.lastname: Strömberg
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D010766:Phosphorylation; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: C415032:picropodophyllin; D011034:Podophyllotoxin