Cheng-Chang Yeh1, Hui-Hsin Ko1,2, Yu-Ping Hsieh1, King-Jean Wu1,2, Mark Yen-Ping Kuo1, Yi-Ting Deng3. 1. School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan. 2. Department of Dentistry, National Taiwan University Hospital, Hsinchu Branch, 25, Lane 442, Sec. 1, Jingguo Rd., Hsinchu, Taiwan. 3. Department of Dentistry, National Taiwan University Hospital, Hsinchu Branch, 25, Lane 442, Sec. 1, Jingguo Rd., Hsinchu, Taiwan. q95422002@ntu.edu.tw.
Abstract
OBJECTIVES: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been regarded as a promising candidate for cancer therapy. However, most of oral cancer cell lines are resistant to the TRAIL-induced cytotoxicity. The aim of this study was to investigate the ability of phenethyl isothiocyanate (PEITC) to sensitize TRAIL-induced apoptosis in TRAIL-resistant oral cancer cells and xenografts. MATERIALS AND METHODS: Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, Western blotting, and a mouse xenograft model were used to study the effects of PEITC and TRAIL on two TRAIL-resistant human oral cancer cells, SAS and Ca9-22. RESULTS: PEITC upregulated death receptor 4 (DR4) and DR5 protein expression and increased reactive oxygen species (ROS) production in both SAS and Ca9-22 cells. Antioxidant N-acetyl-L-cysteine (NAC) and c-Jun NH2-terminal kinase (JNK) inhibitor SP600125 inhibited PEITC-induced DR4 and DR5 expression. Inhibitor experiments showed that PEITC induced apoptosis through ROS-mediated JNK activation and upregulation of DR4 and DR5. Furthermore, treatment with PEITC significantly increased TRAIL-induced apoptosis in both cells. Combined treatment with PEITC and TRAIL had greater effect on the inhibition of tumor growth than either agent alone. CONCLUSIONS: We showed for the first time that PEITC overcomes TRAIL resistance in oral cancer cells and enhance the therapeutic potential of TRAIL in vivo. CLINICAL RELEVANCE: PEITC, either alone or in combination with TRAIL, can be used as a new therapeutic approach for the treatment of oral cancers.
OBJECTIVES:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been regarded as a promising candidate for cancer therapy. However, most of oral cancer cell lines are resistant to the TRAIL-induced cytotoxicity. The aim of this study was to investigate the ability of phenethyl isothiocyanate (PEITC) to sensitize TRAIL-induced apoptosis in TRAIL-resistant oral cancer cells and xenografts. MATERIALS AND METHODS: Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, Western blotting, and a mouse xenograft model were used to study the effects of PEITC and TRAIL on two TRAIL-resistant humanoral cancer cells, SAS and Ca9-22. RESULTS:PEITC upregulated death receptor 4 (DR4) and DR5 protein expression and increased reactive oxygen species (ROS) production in both SAS and Ca9-22 cells. Antioxidant N-acetyl-L-cysteine (NAC) and c-Jun NH2-terminal kinase (JNK) inhibitor SP600125 inhibited PEITC-induced DR4 and DR5 expression. Inhibitor experiments showed that PEITC induced apoptosis through ROS-mediated JNK activation and upregulation of DR4 and DR5. Furthermore, treatment with PEITC significantly increased TRAIL-induced apoptosis in both cells. Combined treatment with PEITC and TRAIL had greater effect on the inhibition of tumor growth than either agent alone. CONCLUSIONS: We showed for the first time that PEITC overcomes TRAIL resistance in oral cancer cells and enhance the therapeutic potential of TRAIL in vivo. CLINICAL RELEVANCE: PEITC, either alone or in combination with TRAIL, can be used as a new therapeutic approach for the treatment of oral cancers.
Entities:
Keywords:
Apoptosis; Death receptors; Oral cancer; PEITC; TRAIL
Authors: K S Satyan; Narasimha Swamy; Don S Dizon; Rakesh Singh; Cornelius O Granai; Laurent Brard Journal: Gynecol Oncol Date: 2006-04-19 Impact factor: 5.482