Imatinib as a key inhibitor of the platelet-derived growth factor receptor mediated expression of cell surface heparan sulfate proteoglycans and functional properties of breast cancer cells.

Cell surface heparan sulfate proteoglycans (HSPGs), syndecans and glypicans, play crucial roles in the functional properties of cancer cells, such as proliferation, adhesion, migration and invasion. Platelet-derived growth factor (PDGF)/PDGF receptor (PDGF-R) mediated signaling, on the other hand, is highly associated with cancer progression. Specifically, PDGF-Rα and PDGF-Rß expressions documented in breast cancer tissue specimens as well as breast cancer cell lines are correlated with tumor aggressiveness and metastasis. Imatinib (Glivec(®)) is a tyrosine kinase inhibitor specific for PDGF-Rs, c-ΚΙΤ and BCR-ABL. In this study we evaluated the effects of imatinib on the properties of breast cancer cells as well as on the expression of HSPGs in the presence and absence of PDGF-BB. These studies have been conducted in a panel of three breast cancer cell lines of low and high metastatic potential. Our results indicate that imatinib exerts a significant inhibitory effect on breast cancer cell proliferation, invasion and migration as well as on the cell surface expression of HSPGs even after exposure of PDGF. These effects depend on the aggressiveness of breast cancer cells and the type of HSPG. It is suggested that imatinib may be of potential therapeutic usefulness in breast cancer regimes.

Small tyrosine kinase inhibitors as key molecules in the expression of metalloproteinases by solid tumors.

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.

Imatinib mesylate inhibits proliferation and exerts an antifibrotic effect in human breast stroma fibroblasts.

Tumor stroma plays an important role in cancer development. In a variety of tumors, such as breast carcinomas, a desmoplastic response, characterized by stromal fibroblast and collagen accumulation, is observed having synergistic effects on tumor progression. However, the effect of known anticancer drugs on stromal cells has not been thoroughly investigated. Imatinib mesylate is a selective inhibitor of several protein tyrosine kinases, including the receptor of platelet-derived growth factor, an important mediator of desmoplasia. Recently, we have shown that imatinib inhibits the growth and invasiveness of human epithelial breast cancer cells. Here, we studied the effect of imatinib on the proliferation and collagen accumulation in breast stromal fibroblasts. We have shown that it blocks the activation of the extracellular signal-regulated kinase and Akt signaling pathways and up-regulates cyclin-dependent kinase inhibitor p21(WAF1), leading to the inhibition of fibroblast proliferation, by arresting them at the G(0)/G(1) phase of the cell cycle. Imatinib inhibits more potently the platelet-derived growth factor-mediated stimulation of breast fibroblast proliferation. By using specific inhibitors, we have found that this is due to the inhibition of the Akt pathway. In addition, imatinib inhibits fibroblast-mediated collagen accumulation. Conventional and quantitative PCR analysis, as well as gelatin zymography, indicates that this is due to the down-regulation of mRNA synthesis of collagen I and collagen III-the main collagen types in breast stroma-and not to the up-regulation or activation of collagenases matrix metalloproteinase 2 and matrix metalloproteinase 9. These data indicate that imatinib has an antifibrotic effect on human breast stromal fibroblasts that may inhibit desmoplastic reaction and thus tumor progression.

A rapid method for fractionation and purification of a 92 kDa cartilage glycoprotein.

Matrix glycoproteins are among the main components that contribute to the properties of cartilage. In this article we report on the development of a rapid method for the fractionation and purification of a 92 kDa glycoprotein from chick sternal cartilage. The developed procedure involves ion-exchange chromatography on DEAE-Sephacel, gel permeation chromatography on Sepharose CL-6B and semi-preparative SDS-polyacrylamide gel electrophoresis. Identification of protein was performed by western blotting using specific antibodies and purity by capillary electrophoresis. The proposed method is superior to those previously published since it eliminates the step of density gradient centrifugation.

Inhibition of receptor tyrosine kinase-based signal transduction as specific target for cancer treatment.

Every cell in a multicellular organism receives signals from the extracellular matrix and neighboring cells. These signals are transmitted, via transmembrane receptors and cascade proteins of the intracellular message system, inside the cell and often to the nucleus, regulating almost every physiological function of the cell. Protein tyrosine kinases constitute a family of receptors that regulate major cellular events, such as cell proliferation, differentiation, cell adhesion and apoptosis. Mutant tyrosine kinases and/or their aberrant activity are associated with human cancer and other hyper-proliferative diseases. Strategies for inhibition of aberrant tyrosine kinase activity, such as antisense oligonucleotides, antigenic stimulation and small molecular inhibitors have been developed. STI571, a phenylaminopyrimidine derivative, is considered to be the pioneer of the small molecular inhibitors available to date. It is a successful tyrosine kinase inhibitor, which is currently approved and used for the treatment of chronic myelogenous leukemia and gastrointestinal tumors. In this article we review the mechanisms of cell signaling, the signal transduction pathways related to tyrosine kinases, their relationship with cancer, and the strategies developed to inhibit the aberrant tyrosine kinase receptor-based signal transduction. Drug resistance and future perspectives for combination therapies are also discussed.