Journal Article

The chemopreventive agent phenethyl isothiocyanate sensitizes cells to Fas-mediated apoptosis

Juliet M. Pullar, Susan J. Thomson, Monica J. King, Christopher I. Turnbull, Robyn G. Midwinter and Mark B. Hampton

in Carcinogenesis

Volume 25, issue 5, pages 765-772
Published in print May 2004 | ISSN: 0143-3334
Published online May 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh063
The chemopreventive agent phenethyl isothiocyanate sensitizes cells to Fas-mediated apoptosis

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The chemopreventive properties of the isothiocyanates have been attributed to their ability to inhibit phase I enzymes that activate procarcinogens, induce phase II protective enzymes and trigger apoptosis in transformed cells. In this study we provide evidence for a new mechanism of chemoprevention, wherein sublethal doses of phenethyl isothiocyanate (PEITC) sensitize cells to Fas-mediated apoptosis. The phenomenon was observed in the Fas-resistant T24 bladder carcinoma cell line and in Jurkat T cells overexpressing the anti-apoptotic protein Bcl-2. Caspase-3-like activity was increased up to 20-fold of that observed with either PEITC or anti-Fas antibody alone. While PEITC activated ERK, JNK and p38, inhibitors of these MAP kinases did not block apoptosis. PEITC transiently depleted cellular glutathione, providing a putative mechanism for sensitizing the cells to apoptosis. However, lowering glutathione with buthionine sulfoximine did not mimic the effect of PEITC. Instead, we propose that PEITC promotes apoptosis by directly modifying intracellular thiol proteins. The ability of PEITC to sensitize cells to receptor-mediated apoptosis provides an additional mechanism to explain its chemopreventive properties.

Keywords: BSO, buthionine sulfoximine; DEVD-AMC, Ac-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin; DISC, death-inducing signal complex; DMSO, dimethylsulfoxide; DPI, diphenyleneiodonium; ERK1/2, extracellular signal-regulated kinase; GSH, reduced glutathione; GSTs, glutathione S-transferases; JNK, c-Jun N-terminal kinase; MAP kinases, mitogen-activated protein kinases; MBB, monobromobimane; PBS, phosphate-buffered saline; PEITC, phenethyl isothiocyanate; PI, propidium iodide; PS, phosphatidylserine

Journal Article.  5886 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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