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Comparative activity of melarsoprol and arsenic trioxide in chronic B-cell leukemia lines
A König1, L Wrazel, R P Warrell
1Sloan-Kettering Institute, the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Abstract:
Inorganic arsenic trioxide (As2O3) was recently shown to induce apoptosis in NB4 promyelocytic leukemic cells. We have investigated the effects of the organic arsenical, melarsoprol (a drug used for treatment of trypanosomiasis), upon induction of apoptosis in cell lines representative of chronic B-cell lymphoproliferative disorders. An Epstein-Barr virus (EBV)-transformed B-prolymphocytic cell line (JVM-2), an EBV-transformed B-cell chronic lymphocytic leukemia (B-CLL) cell line (I83CLL), and one non-EBV-transformed B-CLL cell line (WSU-CLL) were used as targets. Dose-response experiments with melarsoprol (10(-7) to 10(-9) mol/L) were performed over 96 hours. Unexpectedly, we found that melarsoprol caused a dose- and time-dependent inhibition of survival and growth in all three cell lines. In contrast, As2O3 at similar concentrations had no effect on either viability or growth. After 24 hours, all three cell lines treated with melarsoprol (10(-7) mol/L) exhibited morphologic characteristics of apoptosis. We also observed prominent concentration-dependent downregulation of bcl-2 mRNA after 24 hours of exposure to melarsoprol in WSU-CLL, I83CLL, and JVM-2 cells. Decrease of bcl-2 protein expression was also observed in all three cell lines, whereas As2O3 had no effect on this parameter. We conclude that melarsoprol may inhibit the growth of lymphoid leukemic cell by promoting programmed cell death. Results of these studies suggest that melarsoprol shows promising therapeutic activity in these diseases, and a study to evaluate clinical effects of this drug has been initiated.
Insights
Melarsoprol, an anti-trypanosomiasis drug, effectively induces apoptosis and inhibits growth in B-cell leukemia cell lines. This organic arsenical shows promise for treating lymphoid leukemic disorders.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Inorganic arsenic trioxide (As2O3) induces apoptosis in certain leukemia cells.
- Chronic B-cell lymphoproliferative disorders include B-cell chronic lymphocytic leukemia (B-CLL).
- Melarsoprol is an organic arsenical used to treat trypanosomiasis.
Purpose of the Study:
- To investigate the effects of melarsoprol on apoptosis induction in B-cell leukemia cell lines.
- To compare the efficacy of melarsoprol with inorganic arsenic trioxide (As2O3).
Main Methods:
- Three B-cell leukemia cell lines (JVM-2, I83CLL, WSU-CLL) were treated with varying doses of melarsoprol (10(-7) to 10(-9) mol/L) for 96 hours.
- Morphological characteristics of apoptosis were assessed.
- bcl-2 mRNA and protein expression levels were quantified.
Main Results:
- Melarsoprol demonstrated dose- and time-dependent inhibition of survival and growth in all tested cell lines.
- Morphological signs of apoptosis were observed in melarsoprol-treated cells after 24 hours.
- Melarsoprol caused concentration-dependent downregulation of bcl-2 mRNA and protein, unlike As2O3.
Conclusions:
- Melarsoprol effectively inhibits lymphoid leukemic cell growth by promoting programmed cell death (apoptosis).
- These findings suggest melarsoprol possesses promising therapeutic potential for B-cell lymphoproliferative disorders.
- Clinical evaluation of melarsoprol for these conditions has been initiated.