Vorinostat and Sorafenib Synergistically Kill Tumor Cells via FLIP Suppression and CD95 Activation
| Autor: | Hossein A. Hamed, Martin R. Graf, Mohammed Rahmani, Paul Dent, Guo Zhang, Ray Lee, David T. Curiel, Adly Yacoub, Paul B. Fisher, Aditi Pandya Martin, Steven Grant, Clint Mitchell, John D. Roberts, Margaret A. Park |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Niacinamide
Sorafenib Cancer Research Pyridines medicine.drug_class CASP8 and FADD-Like Apoptosis Regulating Protein Apoptosis Hydroxamic Acids urologic and male genital diseases Article Cell Line Tumor Neoplasms Antineoplastic Combined Chemotherapy Protocols medicine Humans fas Receptor FADD neoplasms Vorinostat Protein kinase B Cell Death biology Phenylurea Compounds Benzenesulfonates Histone deacetylase inhibitor Drug Synergism XIAP Cell killing Oncology Cancer research biology.protein medicine.drug |
| Zdroj: | Clinical Cancer Research. 14:5385-5399 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-08-0469 |
| Popis: | Purpose and Design: Mechanism(s) by which the multikinase inhibitor sorafenib and the histone deacetylase inhibitor vorinostat interact to kill hepatic, renal, and pancreatic adenocarcinoma cells has been defined. Results: Low doses of sorafenib and vorinostat interacted in vitro in a synergistic fashion to kill hepatic, renal, and pancreatic adenocarcinoma cells in multiple short-term viability (24-96 h) and in long-term colony formation assays. Cell killing was suppressed by inhibition of cathepsin proteases and caspase-8 and, to a lesser extent, by inhibition of caspase-9. Twenty-four hours after exposure, the activities of extracellular signal-regulated kinase 1/2, AKT, and nuclear factor-κB were only modestly modulated by sorafenib and vorinostat treatment. However, 24 h after exposure, sorafenib- and vorinostat-treated cells exhibited markedly diminished expression of c-FLIP-s, full-length BID, BCL-2, BCL-XL, MCL-1, XIAP, increased expression of BIM, and increased activation of BAX, BAK, and BAD. Expression of eIF2α S51A blocked sorafenib- and vorinostat-induced suppression of c-FLIP-s levels and overexpression of c-FLIP-s abolished lethality. Sorafenib and vorinostat treatment increased surface levels of CD95 and CD95 association with caspase-8. Knockdown of CD95 or FADD expression significantly reduced sorafenib/vorinostat-mediated lethality. Conclusions: These data show that combined exposure of epithelial tumor cell types to sorafenib and vorinostat diminishes expression of multiple antiapoptotic proteins and promotes activation of the CD95 extrinsic apoptotic and the lysosomal protease pathways, and that suppression of c-FLIP-s expression represents a critical event in transduction of the proapoptotic signals from CD95 to promote mitochondrial dysfunction and death. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|