RRC ID 44484
著者 Yamaguchi H, Kidachi Y, Kamiie K, Noshita T, Umetsu H, Fuke Y, Ryoyama K.
タイトル Utilization of 6-(methylsulfinyl)hexyl isothiocyanate for sensitization of tumor cells to antitumor agents in combination therapies.
ジャーナル Biochem Pharmacol
Abstract In the present study, we performed in silico and in vitro analyses to evaluate the chemosensitizing effects of 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) on tumor cells. Our in silico analyses of the ligand-receptor interactions between 6-MITC and the glutamate cysteine ligase (GCL) catalytic subunit (GCLC) revealed that 6-MITC possibly inhibited GCL enzyme activity, and that Cys-249 and Gln-251 were important residues for stable binding of ligands to GCLC. It was further found that 6-MITC interfered with the hydrogen bonds of the cysteinyl and glutamyl moieties of GSH with Cys-249 and Gln-251, respectively, and possibly overrode the feedback inhibition of GCL enzyme activity by GSH. To the best of our knowledge, this is the first in silico analysis to suggest an overriding effect of 6-MITC on GSH-induced feedback inhibition of GCL. In our in vitro analyses, combined treatment with 6-MITC and L-buthionine-S,R-sulfoximine (BSO) depleted GSH within 4 h in tumorigenic human c-Ha-ras and mouse c-myc-cotransfected highly metastatic serum-free mouse embryo-1 (r/m HM-SFME-1) cells, but did not deplete GSH in normal SFME cells. Furthermore, exposure to 6-MITC plus BSO for 4h, followed by glycyrrhetinic acid (GA) treatment for 3h, eradicated the tumor cells with minimal damage to the normal cells. The present findings suggest that 6-MITC in combination therapies could be used to sensitize tumor cells to antitumor agents, thereby leading to their eradication.
巻・号 86(4)
ページ 458-68
公開日 2013-8-15
DOI 10.1016/j.bcp.2013.06.008
PII S0006-2952(13)00379-1
PMID 23791871
MeSH Animals Antineoplastic Agents / pharmacology* Buthionine Sulfoximine / pharmacology* Cell Line Cell Line, Tumor Cell Proliferation / drug effects Computer Simulation Drug Synergism Glutamate-Cysteine Ligase / antagonists & inhibitors* Glutamate-Cysteine Ligase / metabolism Glutathione / metabolism Glycyrrhetinic Acid / pharmacology* Humans Isothiocyanates / pharmacology* Mice Molecular Docking Simulation Protein Subunits / antagonists & inhibitors Protein Subunits / metabolism
IF 4.96
引用数 4
WOS 分野 PHARMACOLOGY & PHARMACY
リソース情報
ヒト・動物細胞 RERF-LC-AI(RCB0444)