title: Utilization of 6-(methylsulfinyl)hexyl isothiocyanate for sensitization of tumor cells to antitumor agents in combination therapies.
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.
authors.affiliation: Department of Pharmacy, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku, Nagoya 468-8503, Japan. hyamagu@meijo-u.ac.jp
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kidachi
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Kamiie
authors.forename: Toshiro
authors.initials: T
authors.lastname: Noshita
authors.forename: Hironori
authors.initials: H
authors.lastname: Umetsu
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fuke
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ryoyama
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004357:Drug Synergism; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000494:pharmacology*; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D051379:Mice; D062105:Molecular Docking Simulation; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C505386:6-(Methylsulfinyl)hexyl isothiocyanate; D000970:Antineoplastic Agents; D017879:Isothiocyanates; D021122:Protein Subunits; D019328:Buthionine Sulfoximine; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D006034:Glycyrrhetinic Acid
keywords: 11-dehydrocorticosterone; 11DHC; 11β-hydroxysteroid dehydrogenase type 2; 11βHSD2; 4-HNE; 4-hydroxynonenal; 6-(Methylsulfinyl)hexyl isothiocyanate (6-MITC); 6-(methylsulfinyl)hexyl isothiocyanate; 6-MITC; ABC; ANOVA; AP-1; ASE-Dock; ATP-binding cassette; BSO; CORT; GA; GCL; GCLC; GCLM; Glutamate cysteine ligase (GCL); Glutamate cysteine ligase catalytic subunit (GCLC); Glutathione (GSH); HCC; ITC; JNK; Jun N-terminal kinase; L-buthionine-S,R-sulfoximine; LBS; LTA4; MOE; MRP1; N-acetyl-l-cysteine; NAC; NF-κB; ROS; SFME; activating protein 1; alpha sphere and excluded volume-based ligand-protein docking; analysis of variance; corticosterone; glutamate cysteine ligase; glutamate cysteine ligase catalytic subunit; glutamate cysteine ligase modifier subunit; glycyrrhetinic acid; human c-Ha-ras and mouse c-myc-cotransfected highly metastatic serum-free mouse embryo-1; human cancer cell; isothiocyanate; leukotriene A4; ligand-binding site; molecular operating environment; multidrug resistance protein 1; nuclear factor κB; r/m HM-SFME-1; reactive oxygen species; serum-free mouse embryo