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Arsenic trioxide sensitivity is associated with low level of glutathione in cancer cells
1Department of Oncology, Graduate Institute of Medicine, National Taiwan University Hospital and Medical College, National Taiwan University, Taipei.
Abstract:
Arsenic trioxide (As2O3) is a novel anticancer agent, which has been found to induce remission in acute promyelocytic leukaemic patients following daily intravenous administration. The therapeutic value of As2O3 in other cancers is still largely unknown. Cytotoxic tests in a panel of cancer cell lines showed that bladder cancer, acute promyelocytic leukaemic and gastrointestinal cancer cells were the most sensitive to As2O3 among 17 cell lines tested. Cellular glutathione (GSH) system plays an important role in arsenic detoxification in mammalian cells. Cancer cells that were intrinsically sensitive to As2O3 contained lower levels of GSH, whereas resistant cancer cells contained higher levels of GSH. On the other hand, there was no association of glutathione-S-transferase-pi or multidrug resistance-associated protein 1 levels with arsenic sensitivity in these cancer cells. Multidrug-resistant cancer cells that were cross-resistant to arsenic contained higher levels of GSH or multidrug-resistance-associated protein 1 than their drug-sensitive parental cells. Cancer cells become more sensitive to arsenic after depletion of cellular GSH with L-buthionine sulphoximine. We concluded that cellular GSH level is the most important determinant of arsenic sensitivity in cancer cells. Cellular GSH level and its modulation by buthionine sulphoximine should be considered in designing clinical trials using arsenic in solid tumours.
Insights
Arsenic trioxide shows promise as an anticancer agent, particularly for bladder, acute promyelocytic leukemia, and gastrointestinal cancers. Cellular glutathione levels are key to arsenic sensitivity, with lower levels indicating higher sensitivity.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Arsenic trioxide (As2O3) is an emerging anticancer therapeutic.
- Its efficacy in various cancers beyond acute promyelocytic leukemia requires further investigation.
- The role of cellular detoxification mechanisms in arsenic response is not fully understood.
Purpose of the Study:
- To evaluate the cytotoxic effects of arsenic trioxide across a broad range of cancer cell lines.
- To determine the relationship between cellular glutathione (GSH) levels and sensitivity to arsenic trioxide.
- To explore the potential of modulating GSH levels to enhance arsenic-induced cancer cell death.
Main Methods:
- Cytotoxicity assays were performed on 17 different cancer cell lines treated with arsenic trioxide.
- Cellular glutathione (GSH) levels were measured in sensitive and resistant cell lines.
- The impact of L-buthionine sulphoximine, a GSH-depleting agent, on arsenic sensitivity was assessed.
Main Results:
- Bladder, acute promyelocytic leukemia, and gastrointestinal cancer cells exhibited the highest sensitivity to arsenic trioxide.
- Intrinsically sensitive cancer cells had lower endogenous GSH levels compared to resistant cells.
- Depletion of cellular GSH using L-buthionine sulphoximine significantly increased cancer cell sensitivity to arsenic trioxide.
Conclusions:
- Cellular glutathione level is a critical determinant of arsenic trioxide sensitivity in cancer cells.
- Modulating GSH levels, potentially with agents like buthionine sulphoximine, could be a strategy to enhance arsenic therapy in solid tumors.
- Further research into GSH's role is warranted for optimizing arsenic-based cancer treatments.