Growth inhibition of human colon cancer cell line HCT116 by bis[2-(acylamino)phenyl] disulfide and its action mechanism.
Our laboratory has been investigating the use of compounds which disrupt beta-catenin/T cell factor (TCF) binding to treat human colon cancer. There are several cysteine residues on the surface of beta-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 beta-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 microM; DLD-1, IC50: 6.9 microM) on cell proliferation, and did not show any cytotoxicity among normal human fibroblast CCD-1059SK cells even at 200 microM. This derivative reduced the beta-catenin/TCF4 association in the HCT116 cells to ca. 50% at 150 microM. Furthermore, it activated markedly the phosphorylation of c-Jun N-terminal kinase (JNK) connected to stress-activated apoptosis at a lower concentration (30 microM). 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.
Yamakawa
Satoshi
S
Department of Life Science and Biotechnology, Faculty of Chemistry, Material and Bioengineering, Kansai University, 3-3-35 Yamate-cho, Suita, Osaka 564-8680, Japan.
Demizu
Aya
A
Kawaratani
Yasuyuki
Y
Nagaoka
Yasuo
Y
Terada
Yuji
Y
Maruyama
Sakiko
S
Uesato
Shinichi
S
D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004220:Disulfides / Q000494:pharmacology*; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D045325:HCT116 Cells; D006801:Humans; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004220:Disulfides; D005456:Fluorescent Dyes; D051176:beta Catenin; C529589:bis(2-(2,2-dimethylpropanoylamino)phenyl)disulfide; D019938:Cyclin D1; D048031:JNK Mitogen-Activated Protein Kinases; C017807:bisbenzimide ethoxide trihydrochloride