Selenite induces apoptosis in sarcomatoid malignant mesothelioma cells through oxidative stress

Free Radical Biology and Medicine. 2006 Sep 15;41(6):874-85. Epub 2006 May 10. [Link]

Gustav Nilsonne^a, Xiaojuan Sun^a, Christina Nyström^a, Anna-Klara Rundlöf^a, Aristi Potamitou Fernandes^a, Mikael Björnstedt^a and Katalin Dobra^{, a,}

^aDepartment of Laboratory Medicine, Karolinska University Hospital, F-46, Karolinska Institutet, S-141 86 Huddinge, Stockholm, Sweden

Abstract

Malignant mesothelioma cells differentiate into sarcomatoid or epithelioid phenotypes. The sarcomatoid cell type is more resistant to chemotherapy and gives a worse prognosis. We have investigated whether selenite alone and in combination with doxorubicin induced apoptosis in variously differentiated mesothelioma cells. Selenite in concentrations that could potentially be administered to patients strongly inhibited the growth of the sarcomatoid mesothelioma cells (IC₅₀ = 7.5 μM), whereas epithelioid cells were more sensitive to doxorubicin. Benign mesothelial cells remained largely unaffected. Selenite potentiated doxorubicin treatment. Apoptosis was the dominating mode of cell death. The toxicity of selenite was mediated by oxidative stress. Furthermore the activity of the thioredoxin system was directly dependent on the concentration of selenite. This offers a possible mechanism of action of selenite treatment. Our findings suggest that selenite is a promising new drug for the treatment of malignant mesothelioma.

Keywords: Mesothelioma; Phenotype; Drug resistance; Apoptosis; Selenium; Thioredoxin reductase; Free radicals

Abbreviations: AB, human AB serum; ASK-1, apoptosis signal regulating kinase-1; DCF, 2′,7′-dichlorodihydrofluorescein diacetate; DCFH-DA, 5(6)-carboxy-2′,7′-dichlorodihydrofluorescein diacetate; DMSO, dimethyl sulfoxide; DTNB, 5,5′-dithiobis(nitrobenzoic acid); EDTA, ethylenediaminetetraacetic acid; FACS, fluorescence-activated cell sorting; FCS, fetal calf serum; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, glutathione (reduced); GSSG, glutathione (oxidized); Hepes, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; PI, propidium iodide; ROS, reactive oxygen species; SEP15, selenoprotein-15; Trx1, thioredoxin-1; TrxR1, thioredoxin reductase 1