Elsevier

Free Radical Biology and Medicine

Volume 41, Issue 6, 15 September 2006, Pages 874-885
Free Radical Biology and Medicine

Original Contribution
Selenite induces apoptosis in sarcomatoid malignant mesothelioma cells through oxidative stress

https://doi.org/10.1016/j.freeradbiomed.2006.04.031Get rights and content

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.

Section snippets

Chemicals

Selenite (Na2SeO3), Tris–HCl, EDTA, Hepes, DMSO, sodium azide (NaN3), H2O2, 5,5′-dithiobis(nitrobenzoic acid) (DTNB), guanidine–HCl, bovine serum albumin, sodium deoxycholate, Biuret reagent, glutathione (GSH), insulin from bovine pancreas, ascorbic acid, 2′,7′-dichlorodihydrofluorescein diacetate (DCF), and NADPH were all purchased from Sigma (St. Louis, MO, USA). Doxorubicin (adriamycin) was obtained from Pharmacia & Upjohn (Stockholm, Sweden). Baker’s yeast glutathione reductase (GR) and

Characterization of cells

The doubling time was comparable between the STAV-AB and the STAV-FCS cell sublines. When the cells were harvested, they were carefully examined to ensure that the growth patterns remained epithelioid and sarcomatoid, respectively. STAV-AB cultures have a cobblestone appearance (Fig. 1A), whereas STAV-FCS cells have a length:width ratio exceeding 2:1 (Fig. 1B). Immunocytochemical analysis showed that the epithelioid STAV-AB cells were strongly reactive to cytokeratin antibodies, but the

Discussion

Malignant mesothelioma is a tumor that may exhibit two phenotypes—epithelioid and sarcomatoid—which seem to have different mechanisms for cancer progression [4] and respond differently to therapy. Presence of the sarcomatoid phenotype in a tumor correlates to therapy resistance and a worse prognosis. Mesothelioma responds poorly and often only partially to treatment [20], [21], which may be explained by the tumor cell heterogeneity. Our previous molecular characterization reveals profound

Acknowledgments

The authors are grateful to Ms. Mervi Nurminen and Ms. Ingrid Norman for skillful technical assistance, as well as to Professor Anders Hjerpe for his unfailing support in all aspects of this study. This study was supported by grants from the Swedish Cancer and Allergy Fund, the Swedish Society of Medicine, and the Swedish Heart and Lung Association.

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