Concluding remarks Our results clearly demonstrate that selenite causes a complex pattern of cell death in malignant mesothelioma cells. Selenite causes Selleckchem FHPI both apoptosis and necrosis, but cells exhibiting apoptotic characteristics such as Annexin V externalisation do not necessarily display other classical apoptosis-related changes such as caspase-activation [6, 18, 40]. It appears purposeful to consider selenite-induced cell death to

lie on a spectrum between apoptosis and necrosis, where the exact mode of cell death differs depending on phenotype characteristics. Our results indicate that mesothelioma cells activate p38 and JNK in response to selenite, and that they accumulate p53 in the nucleus, but in a form bereft of DNA-binding activity. We hypothesise that this interesting phenomenon is due to a shift in redox balance towards a prooxidative state with increased levels of reactive oxygen species (ROS) and a loss of thioredoxin system activity. Sarcomatoid mesothelioma cells, although ordinarily chemoresistant, are more sensitive to selenite than epithelioid cells [1]. The differential activation of apoptosis-signaling proteins on the level of the mitochondrion may partially explain the observed differences in sensitivity. A better understanding of the proapoptotic mechanisms of selenite as well as of phenotype-dependent response patterns in mesothelioma cells

will aid the development Buparlisib of Selleck KU55933 Cancer therapies with greater efficacy and which may be better suited to the diverse biology of individual tumors. Malignant mesothelioma is a heterogeneous entity, and further studies on differentiation-related sensitivity to selenite and other cytotoxic drugs are under way in our laboratory using a panel of cell lines of varying epithelioid-sarcomatoid differentiation. Acknowledgements

The authors are grateful to Mervi Nurminen, Gunilla Fahlström, and Anette Hofmann for their expert technical assistance, and to Kristin Gustafsson. This study has been supported by the Swedish Foundation for Strategic Research, the Swedish Heart and Lung foundation, the Swedish Cancer Fund, and the Swedish Cancer and Allergy Fund. Electronic supplementary material Additional file 1: Internal verification of the efficacy of apoptosis signalling enzyme inhibitors. An internal Tenofovir concentration verification of the efficacy of the inhibitors was established by their ability to reduce apoptosis in the control cells. Two-way ANOVA with Dunnett’s post test was used to compare the apoptosis frequency with the respective inhibitors to that in the control cells without any inhibitor. Asterisks denote p < 0.05. Data represent the same three independent experiments illustrated in figure 1. Bars indicate the standard error of the mean. (PDF 21 KB) Additional file 2: External verification of the efficacy of apoptosis signalling enzyme inhibitors. A-E: Apoptosis kinetics of Jurkat cells treated with staurosporine and chemical inhibitors, to verify that the inhibitors were able to alter the apoptotic rate.