摘要：Our laboratory has been investigating the use of compounds which disrupt β-catenin/T cell factor (TCF) binding to treat human colon cancer. There are several cysteine residues on the surface of β-catenin where it binds to TCF. Some bis[2-(acylamino)phenyl] disulfides might have the ability to form a disulfide bond with the cysteine residues of β-catenin, leading to inhibition of the growth of human colon cells. Bis[2-(acylamino)phenyl] disulfides were screened to inhibit the growth of cancer cells. Among them, bis[2-(2,2-dimethylpropanoylamino)phenyl] disulfide (1) had promising inhibitory effects (HCT116, IC50: 9.7 μ M ; DLD-1, IC50: 6.9 μ M ) on cell proliferation, and did not show any cytotoxicity among normal human fibroblast CCD-1059SK cells even at 200 μ M . This derivative reduced the β-catenin/TCF4 association in the HCT116 cells to ca. 50% at 150 μ M . Furthermore, it activated markedly the phosphorylation of c-Jun N-terminal kinase (JNK) connected to stress-activated apoptosis at a lower concentration (30 μ M ). In view of cell cycle analyses, Hoechst staining, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin Nick end-labeling (TUNEL) assays along with the above results, it is likely that 1 inhibited the growth of HCT116 cells through pathways including the JNK-mediated apoptosis.
关键词：HCT116;bis[2-(acylamino)phenyl] disulfide;c-Jun N-terminal kinase;apoptosis;β-catenin/T cell factor association
