title: Imatinib inhibits colorectal cancer cell growth and suppresses stromal-induced growth stimulation, MT1-MMP expression and pro-MMP2 activation.
abstract: Tumor progress depends on the proliferation of cancer cells, their interactions with stroma and the proteolytic action of enzymes. Colon cancer is c-kit positive and responsive to the specific tyrosine kinase inhibitor imatinib. We investigated the effect of imatinib on the proliferation of a panel of epithelial colon cancer cell lines in presence and absence of the antimetabolite 5-FU, and the effect of conditioned media (CM) derived from colon stromal fibroblasts with and without previous exposure to imatinib. The effects of imatinib on gene expression of MMPs and TIMPs were also studied. Imatinib effectively inhibited the proliferation of all cell lines, showing IC(50) from 0.3 to 3 microM. Its combination with 5-FU significantly enhances the growth inhibition of the highly tumourigenic HT-29 cells. CM derived from stromal fibroblasts induced the proliferation of the HT-29 cells; this stimulatory effect was abolished upon treatment with CM obtained after exposure of fibroblasts to imatinib. Gene expression of MT1-, MT2-MMP and MMP-7 was also inhibited depending on the cell line, whereas that of TIMP-2 was not affected. CM stimulated MT1-MMP protein expression by HT-29; this stimulatory effect was suppressed in the presence of imatinib. Activation of pro-MMP2 to MMP2 in culture medium of HT-29 treated with CM was increased and this activity was inhibited in presence of imatinib. The obtained data showed that imatinib is a powerful inhibitor of human colon cancer cell growth and effectively suppresses the stromal-induced stimulation of cancer cell growth and activation of proMMP2. Further studies are warranted to evaluate the in vivo effects.
authors.affiliation: Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece.
authors.forename: Xanthi N
authors.initials: XN
authors.lastname: Stahtea
authors.forename: Andeas E
authors.initials: AE
authors.lastname: Roussidis
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kanakis
authors.forename: George N
authors.initials: GN
authors.lastname: Tzanakakis
authors.forename: George
authors.initials: G
authors.lastname: Chalkiadakis
authors.forename: Dimitris
authors.initials: D
authors.lastname: Mavroudis
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kletsas
authors.forename: Nikos K
authors.initials: NK
authors.lastname: Karamanos
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000187:drug effects / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology*; D018093:Gelatinases / Q000187:drug effects / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D053511:Matrix Metalloproteinase 14 / Q000187:drug effects / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D004792:Enzyme Precursors; D010879:Piperazines; D011743:Pyrimidines; D019714:Tissue Inhibitor of Metalloproteinases; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase; D053511:Matrix Metalloproteinase 14; D005472:Fluorouracil