Journal Article

Benzyl isothiocyanate inhibits excessive superoxide generation in inflammatory leukocytes: implication for prevention against inflammation-related carcinogenesis

Noriyuki Miyoshi, Satoko Takabayashi, Toshihiko Osawa and Yoshimasa Nakamura

in Carcinogenesis

Volume 25, issue 4, pages 567-575
Published in print April 2004 | ISSN: 0143-3334
Published online April 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh051
Benzyl isothiocyanate inhibits excessive superoxide generation in inflammatory leukocytes: implication for prevention against inflammation-related carcinogenesis

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Inhibitors of excessive superoxide ([math]) generation have been indicated to be more effective antioxidants than radical scavengers because [math] anion is one of the precursors of several types of reactive oxygen species (ROS). We demonstrated here that benzyl isothiocyanate (BITC) is a potent inhibitor of leukocytic NADPH oxidase generating a great amount of [math] in oxidative burst. The exposure of BITC to the differentiated HL-60 cells resulted in the inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced [math] generation, while the methylthiocarbamate analog of BITC, hardly reactive with thiols including glutathione and protein sulfhydryl, did not show any effect. Pre-treatment of the cells with diethyl maleate significantly potentiated the BITC-induced inhibition, while pre-treatment with N-acetyl-cysteine counteracted it. These results led us to assume that a plausible intracellular target molecule(s) having a reactive sulfhydryl moiety might be regulated by the covalent attachment with BITC. In spite of no ability to affect the translocation of protein kinase C β to the membrane, BITC probably modifies the electron transport system of cytochrome b558, consistent with the observation that BITC inhibited the substrate utilization. Pre-treatments of mouse skin with BITC significantly attenuated the TPA-enhanced hydrogen peroxide level, suggesting that BITC indeed acts as an inhibitor of [math] generation in mouse skin. A histological study also demonstrated that BITC inhibited TPA-induced leukocyte infiltration in the dermis. Because we have found several [math] generation inhibitors to be effective chemopreventors against mouse skin carcinogenesis, the modifying effect of the topical application of BITC on TPA-induced mouse skin tumor promotion was investigated. We demonstrated for the first time that the pre-treatment with BITC 40 min prior to each TPA treatment significantly inhibited the number of papillomas per mouse. In conclusion, the results from this study provided biological evidence that BITC has a potential to prevent inflammation-related carcinogenesis including skin cancer.

Keywords: BITC, benzyl ITC; BITC-OMe, O-methyl benzylthiocarbamate; DEM, diethyl maleate; DMBA, dimethylbenz[a]anthracene; DMSO, dimethylsulfoxide; DTNB, 5,5′-dithiobis(2-nitrobenzoic acid); GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GSH, glutathione; GST, glutathione S-transferase; H2O2, hydrogen peroxide; ITCs, isothiocyanates; MPO, myeloperoxidase; NAC, N-acetyl-cysteine; \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{O}_{2}^{{-}}\) \end{document}, superoxide; PKC, protein kinase C; ROS, reactive oxygen species; TPA, 12-O-tetradecanoylphorbol-13-acetate

Journal Article.  7714 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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