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

• Published in: Carcinogenesis (New York) 2004-05, Vol.25 (5), p.765-772
• Main Authors: Pullar, Juliet M., Thomson, Susan J., King, Monica J., Turnbull, Christopher I., Midwinter, Robyn G., Hampton, Mark B.
• Format: Article
• Language: English
• Subjects: Ac-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin; Aldehyde Dehydrogenase - antagonists & inhibitors; Anticarcinogenic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; BSO; buthionine sulfoximine; Buthionine Sulfoximine - pharmacology; c-Jun N-terminal kinase; Carcinogenesis, carcinogens and anticarcinogens; Caspase 3; Caspases - metabolism; Chemical agents; Chemoprevention; death-inducing signal complex; DEVD-AMC; dimethylsulfoxide; diphenyleneiodonium; DISC; DMSO; DPI; Drug Resistance, Neoplasm; ERK1/2; extracellular signal-regulated kinase; fas Receptor - metabolism; glutathione S-transferases; GSH; GSTs; Humans; Isothiocyanates - pharmacology; JNK; JNK Mitogen-Activated Protein Kinases; Jurkat Cells; MAP Kinase Kinase 4; MAP kinases; MBB; Medical sciences; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases - metabolism; mitogen-activated protein kinases; Mitogen-Activated Protein Kinases - metabolism; monobromobimane; p38 Mitogen-Activated Protein Kinases; PBS; PEITC; phenethyl isothiocyanate; phosphate-buffered saline; phosphatidylserine; propidium iodide; Proto-Oncogene Proteins c-bcl-2 - metabolism; reduced glutathione; Signal Transduction; Tumors; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgh063

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.