High-Throughput Drug Screen Identifies Chelerythrine as a Selective Inducer of Death in a TSC2-null Setting
| Autor: | Chenggang Li, Carmen Priolo, Jane J. Yu, Andrey A. Parkhitko, Damir Khabibullin, Murugabaskar Balan, Yang Sun, Soumitro Pal, Elizabeth P. Henske, Douglas A. Medvetz, John M. Asara |
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| Rok vydání: | 2015 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Cancer Research Programmed cell death Necroptosis mTORC1 Mechanistic Target of Rapamycin Complex 1 Biology Pharmacology Article chemistry.chemical_compound Tuberous Sclerosis In vivo Cell Line Tumor Tuberous Sclerosis Complex 2 Protein Humans Molecular Biology Benzophenanthridines Sirolimus Cell Death TOR Serine-Threonine Kinases Tumor Suppressor Proteins Glutathione nervous system diseases Oxidative Stress Chelerythrine Oncology chemistry Cell culture Multiprotein Complexes Cancer research Drug Screening Assays Antitumor TSC2 Reactive Oxygen Species Heme Oxygenase-1 |
| Zdroj: | Molecular Cancer Research. 13:50-62 |
| ISSN: | 1557-3125 1541-7786 |
| Popis: | Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome associated with tumors of the brain, heart, kidney, and lung. The TSC protein complex inhibits the mammalian or mechanistic target of rapamycin complex 1 (mTORC1). Inhibitors of mTORC1, including rapamycin, induce a cytostatic response in TSC tumors, resulting in temporary disease stabilization and prompt regrowth when treatment is stopped. The lack of TSC-specific cytotoxic therapies represents an important unmet clinical need. Using a high-throughput chemical screen in TSC2-deficient, patient-derived cells, we identified a series of molecules antagonized by rapamycin and therefore selective for cells with mTORC1 hyperactivity. In particular, the cell-permeable alkaloid chelerythrine induced reactive oxygen species (ROS) and depleted glutathione (GSH) selectively in TSC2-null cells based on metabolic profiling. N-acetylcysteine or GSH cotreatment protected TSC2-null cells from chelerythrine's effects, indicating that chelerythrine-induced cell death is ROS dependent. Induction of heme-oxygenase-1 (HMOX1/HO-1) with hemin also blocked chelerythrine-induced cell death. In vivo, chelerythrine inhibited the growth of TSC2-null xenograft tumors with no evidence of systemic toxicity with daily treatment over an extended period of time. This study reports the results of a bioactive compound screen and the identification of a potential lead candidate that acts via a novel oxidative stress–dependent mechanism to selectively induce necroptosis in TSC2-deficient tumors. Implications: This study demonstrates that TSC2-deficient tumor cells are hypersensitive to oxidative stress–dependent cell death, and provide critical proof of concept that TSC2-deficient cells can be therapeutically targeted without the use of a rapalog to induce a cell death response. Mol Cancer Res; 13(1); 50–62. ©2014 AACR. |
| Databáze: | OpenAIRE |
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