Growth Inhibition of Human Colon Cancer Cell Line HCT116 by Bis[2-(acylamino)phenyl] Disulfide and Its Action Mechanism(Pharmacognosy)

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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, IC_<50>: 9.7 μM; DLD-1, IC_<50>: 6.9 μM) on cell proliferation, and did not show any cytotoxicity among normal human fibroblast CCD-1059SK cells even at 200 μM. This derivative reduced the β-catenin/TCF4 association in the HCT116 cells to ca. 50% at 150 μM. Furthermore, it activated markedly the phosphorylation of c-Jun N-terminal kinase (JNK) connected to stress-activated apoptosis at a lower concentration (30 μM). In view of cell cycle analyses, Hoechst staining, and terminal deoxynucleotidyltransferase-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.
公益社団法人日本薬学会の論文
2008-05-01