| Summary: | 碩士 === 國立中央大學 === 生命科學研究所 === 89 === Protein Tyrosine Kinases (PTKs) play a key role in normal cell and tissue development. However, enhanced PTK activity is correlated with proliferative diseases, such as cancers, leukemias, psoriasis, and restenosis. Recently, PTKs have emerged as crucial targets for therapeutic intervention in cancers. In the signal transduction pathways, growth factor ligands and their respective receptor tyrosine kinases (RTKs) have been shown to be required for tumor cell growth. This realization have prompted bioorganic chemists to systematically synthesize tyrosine kin- ase inhibitors.
In this study, we have applied a panel of cyclic-peptidomimetic compounds 2,5-dioxopiperazine derivatives(provided by Dr. Lee), and attempted to screen their growth inhibitory effect on tumor cells. Furthermore, we will also take a shot at organizing the relationship of cyclic-peptidomimetic compounds structure and inhibitory effect. Among these, p194, p185, C1, p206 and p236-3 showed promising inhibitory effect on tumor cell growth with IC50= 110-130 mM, 90 mM, 100 mM, 5-7 mM and 45-55 mM respectively. p194, p185 and C1 had no significantly effect on protein phosphorylation profile on tyrosine residues. In contrast, p206 treatment on H460 cells did alter several proteins phosphorylation and resulted in mitosis-arrest. The degradation of spindle protein Mad2 was also significantly inhibited by p206 treatment in H460 cells.
Although, p236-3 had no effect on cell cycle progress, it showed differential cytotoxicity between tumor and normal fibroblast cells. p236-3 almost had no inhibitory effect on human normal fibroblast cells. The Western blotting results with phosphotyrosine antibody showed that this compound dose-dependently enhanced the phosphorylation level of two proteins around 70 and 60 kDa. These results suggest that p236-3 may be an inhibitor of phosphatase, instead of tyrosine kinase. The inhibitory mechanism of p236-3 and the two proteins (70 and 60 kDa) deserves for further investigation.
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