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[Mechanism of arsenic trioxide-induced cytotoxicity on multiple myeloma cells]
Yu-Bao Chen1, Jian Hou, Wei-Jun Fu
1Department of Hematology, Changzheng Hospital, The Second Military Medical University, Shanghai, PR China. cybllx@sh163.net
Background & Objective:
Multiple myeloma (MM), a plasma cell tumor, is difficult to cure by now. Previous study showed that As2O3 could inhibit the proliferation and induce the apoptosis of myeloma cell in vitro. The aim of this study was to explore the possible mechanism of arsenic trioxide (As2O3) on multiple myeloma cells.
Methods:
The cytotoxic effects of As2O3 on five myeloma cell lines U266, SKO-007, LP-1, HS-Sultan, and KM3 were examined using MTT bioassay, and the concentration of 50% growth inhibition (IC(50)) was calculated. The synergistic or antagonistic effects of menadione (VK(3)), N-acetyl-cysteine (NAC), and reduced glutathione (GSH) combined with As2O3 were also examined. The cellular GSH levels in five MM cell lines and its changes in U266 cells after treated with As2O3, VK(3), NAC, and exogenous GSH were determined by colorimetric assay, and the relationship between IC(50) and cellular GSH levels was analyzed.
Results:
As2O3 inhibited the proliferation of all five myeloma cells, but with different sensitivity. GSH contents in five MM cells were correlated with its IC(50) significantly (r=0.87,P< 0.05). Oxidant VK(3) had significant synergistic effect with As2O3, and antioxidants NAC and GSH partly blocked the growth inhibition of As2O3. Both As2O3 and VK(3) decreased the GSH contents, NAC and GSH increased them contrarily.
Conclusion:
One of the mechanisms of effect of As2O3 on myeloma cells may be through decreasing the cellular GSH levels and inducing myeloma cell apoptosis.
Insights
Arsenic trioxide (As2O3) inhibits multiple myeloma (MM) cell growth by reducing cellular glutathione (GSH) levels. This mechanism contributes to inducing apoptosis in these cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multiple myeloma (MM) is a challenging plasma cell malignancy with limited curative options.
- Arsenic trioxide (As2O3) has demonstrated in vitro potential to inhibit myeloma cell proliferation and induce apoptosis.
- Understanding the precise mechanisms of As2O3 action is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the underlying mechanisms by which arsenic trioxide (As2O3) exerts its effects on multiple myeloma (MM) cells.
- To explore the role of cellular glutathione (GSH) levels in mediating the anti-myeloma activity of As2O3.
Main Methods:
- Cytotoxic effects of As2O3 on five MM cell lines (U266, SKO-007, LP-1, HS-Sultan, KM3) were assessed using MTT assays to determine IC(50) values.
- Synergistic/antagonistic effects of As2O3 with menadione (VK(3)), N-acetyl-cysteine (NAC), and reduced glutathione (GSH) were evaluated.
- Cellular GSH levels were measured, and their correlation with As2O3 sensitivity was analyzed.
Main Results:
- As2O3 demonstrated inhibitory effects on all tested MM cell lines with varying sensitivities.
- A significant correlation was found between cellular GSH content and the IC(50) of As2O3 (r=0.87, P<0.05).
- The oxidant VK(3) synergized with As2O3, while antioxidants NAC and GSH partially reversed As2O3-induced growth inhibition, indicating GSH's role.
Conclusions:
- A key mechanism of As2O3's anti-myeloma effect involves the reduction of intracellular GSH levels.
- Decreased GSH levels induced by As2O3 likely contribute to the apoptosis of multiple myeloma cells.
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