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Selenite-induced apoptosis in doxorubicin-resistant cells and effects on the thioredoxin system
Kerstin Jönsson-Videsäter1, Linda Björkhem-Bergman, Akter Hossain
1Division of Hematology and Oncology, Department of Medicine, Karolinska Institutet, Huddinge University Hospital, Stockholm SE-141 86, Sweden.
Abstract:
Selenium treatment of the doxorubicin-resistant cell line, U-1285dox, derived from human small cell carcinoma of the lung, resulted in massive apoptosis. This effect appeared maximal at 2 days after addition of selenite. The apoptosis was caspase-3 independent as revealed by Western blot analysis, activity measurement and by using caspase inhibitors. Induction of apoptosis was significantly more pronounced and occurred after addition of lower concentrations of selenite in the doxorubicin-resistant cells compared to the parental doxorubicin-sensitive cells. High levels of selenite caused necrosis in the doxorubicin-sensitive cells. Analysis of enzymatic activity (insulin reduction) of thioredoxin reductase (TrxR) and TrxR protein concentration, measured by ELISA, revealed increasing activity and protein levels after treatment with increasing concentrations of selenium. Maximum relative increase was induced up to 1 microM in both sublines and at this selenium level the concentrations of TrxR measured as insulin reducing activity or ELISA immunoreactivity were nearly identical. Increasing concentrations of selenite up to 10 microM resulted in increased activity and concentration of TrxR in the sensitive subline but decreasing levels in the resistant subline. The level of truncated Trx (tTrx) was higher in the resistant U-1285dox cells but the level did not change with increasing selenite concentrations. Our results demonstrate pronounced selective selenium-mediated apoptosis in therapy-resistant cells and suggest that redox regulation through the thioredoxin system is an important target for cancer therapy.
Insights
Selenium selectively induces apoptosis in drug-resistant lung cancer cells, independent of caspase-3. This suggests targeting the thioredoxin system with selenium could be a novel cancer therapy approach.
Area of Science:
- Oncology
- Biochemistry
- Cell Biology
Background:
- Doxorubicin resistance is a major challenge in small cell lung carcinoma treatment.
- Selenium's role in cancer therapy is under investigation, particularly its redox regulatory mechanisms.
Purpose of the Study:
- To investigate the selective effects of selenium (selenite) on doxorubicin-resistant (U-1285dox) versus doxorubicin-sensitive lung cancer cells.
- To elucidate the mechanism of selenium-induced apoptosis, focusing on caspase-3 independence and the thioredoxin reductase system.
Main Methods:
- Cell culture of doxorubicin-resistant and sensitive human small cell lung carcinoma lines.
- Treatment with varying concentrations of selenite.
- Apoptosis assessment via Western blot, activity assays, and caspase inhibitors.
- Thioredoxin reductase (TrxR) activity and protein levels measured by insulin reduction assay and ELISA.
- Analysis of truncated thioredoxin (tTrx) levels.
Main Results:
- Selenite induced massive, caspase-3 independent apoptosis in doxorubicin-resistant cells, more pronounced than in sensitive cells.
- High selenite concentrations caused necrosis in sensitive cells.
- Selenium treatment increased TrxR activity and protein levels up to 1 microM in both cell lines.
- Beyond 1 microM, TrxR levels decreased in resistant cells but increased in sensitive cells.
- Truncated Trx (tTrx) was higher in resistant cells but unaffected by selenite.
Conclusions:
- Selenium exhibits selective apoptosis-inducing effects in therapy-resistant lung cancer cells.
- The thioredoxin system is implicated in selenium's mechanism and represents a potential therapeutic target in cancer treatment.
- Selenium-mediated redox regulation offers a promising strategy for overcoming drug resistance.
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