1. Thiourea compound AW00178 sensitizes human H1299 lung carcinoma cells to TRAIL-mediated apoptosis.
- Author
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Ryu BJ, Hwang MK, Park M, Lee K, and Kim SH
- Subjects
- Adenocarcinoma, Adenocarcinoma of Lung, Apoptosis genetics, Cell Line, Tumor, Drug Resistance, Neoplasm genetics, Drug Synergism, Humans, Inhibitor of Apoptosis Proteins genetics, Inhibitor of Apoptosis Proteins metabolism, JNK Mitogen-Activated Protein Kinases genetics, JNK Mitogen-Activated Protein Kinases metabolism, Lung Neoplasms, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction drug effects, Signal Transduction genetics, Survivin, Thiourea pharmacology, Transcription Factor CHOP genetics, Transcription Factor CHOP metabolism, Antineoplastic Agents pharmacology, Apoptosis drug effects, Drug Resistance, Neoplasm drug effects, Gene Expression Regulation, Neoplastic drug effects, Pyrazoles pharmacology, TNF-Related Apoptosis-Inducing Ligand pharmacology, Thiourea analogs & derivatives
- Abstract
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in a wide variety of cancer cells. Recently, cancer cell resistance to TRAIL-mediated apoptosis has become a challenging issue in the development of TRAIL-based anti-cancer therapies. In this study, we found that 1-(5-chloro-2-methyl-phenyl)-3-[4-(5-trifluoromethyl-pyrazol-1-yl)-phenyl]-thiourea (AW00178) was able to sensitize TRAIL-resistant human lung cancer H1299 cells to TRAIL-mediated apoptosis. Treatment with AW00178, either alone or in combination with TRAIL, induced the expression of CHOP, a protein related to TRAIL sensitivity, and reduced the expression of survivin, an anti-apoptotic protein involved in TRAIL resistance. Additionally, AW00178, alone or in combination with TRAIL, induced the activation of c-Jun and inactivation of Akt. A pharmacologic inhibition study revealed that c-Jun activation and Akt inactivation were strongly related to CHOP induction and survivin down-regulation, respectively. In summary, these results suggested that AW00178 mediated sensitization to TRAIL-mediated apoptosis in H1299 cells by increasing sensitivity and decreasing resistance to TRAIL via the induction of c-Jun-dependent CHOP expression and the reduction of Akt-dependent survivin expression, respectively., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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