RESUMO
Critical steps for cancer cell growth, migration, invasion, and metastasis are the interactions of extracellular matrix (ECM) molecules with cells, the disconnection of intercellular adhesion, and the degradation of ECM. The latter is mediated mainly by metalloproteinases (MMPs), the expression and activation of which is related to various tyrosine kinase receptors (RTKs). The aberrant RTK activity is associated with the development and progress of various human cancers. Tyrosine kinase inhibitors (TKIs) are small molecules which compete with ATP for binding to the kinase domain of the RTKs and have been used for the treatment of solid tumors. In this review, the recent advances of the effects of TKIs on MMPs expressed by solid tumors are presented.
Assuntos
Metaloproteases/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Progressão da Doença , Humanos , Metaloproteases/antagonistas & inibidores , Neoplasias/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/metabolismoRESUMO
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.