Selenite induces apoptosis in sarcomatoid malignant mesothelioma cells through oxidative stress.
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 microM), 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.
Nilsonne
Gustav
G
Department of Laboratory Medicine, Karolinska University Hospital, F-46, Karolinska Institutet, S-141 86 Huddinge, Stockholm, Sweden.
Sun
Xiaojuan
X
Nyström
Christina
C
Rundlöf
Anna-Klara
AK
Potamitou Fernandes
Aristi
A
Björnstedt
Mikael
M
Dobra
Katalin
K
D000230:Adenocarcinoma; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D008654:Mesothelioma / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D018038:Sodium Selenite / Q000633:toxicity*; D013438:Sulfhydryl Compounds / Q000378:metabolism
D013438:Sulfhydryl Compounds; D005979:Glutathione Peroxidase; D018038:Sodium Selenite