A Small Molecule SMAC Mimic LBW242 Potentiates TRAIL- and Anticancer Drug-Mediated Cell Death of Ovarian Cancer Cells

BACKGROUND: Ovarian cancer remains a leading cause of death in women and development of new therapies is essential. Second mitochondria derived activator of caspase (SMAC) has been described to sensitize for apoptosis. We have explored the pro-apoptotic activity of LBW242, a mimic of SMAC/DIABLO, on ovarian cancer cell lines (A2780 cells and its chemoresistant derivative A2780/ADR, SKOV3 and HEY cells) and in primary ovarian cancer cells. The effects of LBW242 on ovarian cancer cell lines and primary ovarian cancer cells was determined by cell proliferation, apoptosis and biochemical assays. PRINCIPAL FINDINGS: LBW242 added alone elicited only a moderate pro-apoptotic effect; however, it strongly synergizes with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or anticancer drugs in inducing apoptosis of both ovarian cancer cell lines and primary ovarian cancer cells. Mechanistic studies show that LBW242-induced apoptosis in ovarian cancer cells is associated with activation of caspase-8. In line with this mechanism, c-FLIP overexpression inhibits LBW242-mediated apoptosis. CONCLUSION: LBW242 sensitizes ovarian cancer cells to the antitumor effects of TRAIL and anticancer drugs commonly used in clinic. These observations suggest that the SMAC/DIABLO mimic LBW242 could be of value for the development of experimental strategies for treatment of ovarian cancer

Silicon detectors for the sLHC

In current particle physics experiments, silicon strip detectors are widely used as part of the inner tracking layers. A foreseeable large-scale application for such detectors consists of the luminosity upgrade of the Large Hadron Collider (LHC), the super-LHC or sLHC, where silicon detectors with extreme radiation hardness are required. The mission statement of the CERN RD50 Collaboration is the development of radiation-hard semiconductor devices for very high luminosity colliders. As a consequence, the aim of the RandD programme presented in this article is to develop silicon particle detectors able to operate at sLHC conditions. Research has progressed in different areas, such as defect characterisation, defect engineering and full detector systems. Recent results from these areas will be presented. This includes in particular an improved understanding of the macroscopic changes of the effective doping concentration based on identification of the individual microscopic defects, results from irradiation with a mix of different particle types as expected for the sLHC, and the observation of charge multiplication effects in heavily irradiated detectors at very high bias voltages. © 2011 Elsevier B.V

Silicon detectors for the sLHC

In current particle physics experiments, silicon strip detectors are widely used as part of the inner tracking layers. A foreseeable large-scale application for such detectors consists of the luminosity upgrade of the Large Hadron Collider (LHC), the super-LHC or sLHC, where silicon detectors with extreme radiation hardness are required. The mission statement of the CERN RD50 Collaboration is the development of radiation-hard semiconductor devices for very high luminosity colliders. As a consequence, the aim of the R&D programme presented in this article is to develop silicon particle detectors able to operate at sLHC conditions. Research has progressed in different areas, such as defect characterisation, defect engineering and full detector systems. Recent results from these areas will be presented. This includes in particular an improved understanding of the macroscopic changes of the effective doping concentration based on identification of the individual microscopic defects, results from irradiation with a mix of different particle types as expected for the sLHC, and the observation of charge multiplication effects in heavily irradiated detectors at very high bias voltages. (C) 2011 Elsevier B.V. All rights reserved

Silicon detectors for the sLHC

In current particle physics experiments, silicon strip detectors are widely used as part of the inner tracking layers. A foreseeable large-scale application for such detectors consists of the luminosity upgrade of the Large Hadron Collider (LHC), the super-LHC or sLHC, where silicon detectors with extreme radiation hardness are required. The mission statement of the CERN RD50 Collaboration is the development of radiation-hard semiconductor devices for very high luminosity colliders. As a consequence, the aim of the R&D programme presented in this article is to develop silicon particle detectors able to operate at sLHC conditions. Research has progressed in different areas, such as defect characterisation, defect engineering and full detector systems. Recent results from these areas will be presented. This includes in particular an improved understanding of the macroscopic changes of the effective doping concentration based on identification of the individual microscopic defects, results from irradiation with a mix of different particle types as expected for the sLHC, and the observation of charge multiplication effects in heavily irradiated detectors at very high bias voltages. (C) 2011 Elsevier B.V. All rights reserved