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HPLC-based Assay to Monitor Extracellular Nucleotide/Nucleoside Metabolism in Human Chronic Lymphocytic Leukemia Cells
Published on: July 20, 2016
Lysosomotropic agents selectively target chronic lymphocytic leukemia cells due to altered sphingolipid metabolism
R F Dielschneider1,2, H Eisenstat2, S Mi3
1Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
Abstract:
Lysosome membrane permeabilization (LMP) mediates cell death in a variety of cancer cells. However, little is known about lysosomes and LMP in chronic lymphocytic leukemia (CLL). Owing to drug resistance and toxicity in CLL patients, better treatment strategies are required. Our results show that CLL cells were sensitive to the lysosomotropic agent siramesine. Furthermore, this drug was more effective in CLL cells, regardless of prognostic factors, compared with normal B cells. Siramesine caused LMP, lipid peroxidation and transcription factor EB nuclear translocation followed by mitochondrial membrane potential loss and reactive oxygen species release. Siramesine-induced cell death was blocked by lipid antioxidants, but not by soluble antioxidants or protease inhibitors. To determine whether CLL cells had altered lysosomes, we investigated sphingolipid metabolism as the lysosome is a hub for lipid metabolism. We found that CLL cells had more lysosomes, increased sphingosine-1-phosphate phosphatase 1 (SPP1) expression, and increased levels of sphingosine compared with normal B cells. Raising sphingosine levels increased LMP and cell death in CLL cells, but not in normal B cells. Together, these results show that excess sphingosine in CLL cells could contribute to their sensitivity toward LMP. Thus, targeting the lysosome could be a novel therapeutic strategy in CLL.
Insights
Chronic lymphocytic leukemia (CLL) cells show increased sensitivity to siramesine, a drug targeting lysosome membrane permeabilization (LMP). This sensitivity is linked to elevated sphingosine levels, suggesting lysosomes as a novel therapeutic target for CLL.
Area of Science:
- Cell Biology
- Cancer Research
- Biochemistry
Background:
- Lysosome membrane permeabilization (LMP) is a known cell death pathway in cancer.
- Chronic lymphocytic leukemia (CLL) presents challenges due to drug resistance and toxicity.
- Understanding lysosome function in CLL is crucial for developing new treatments.
Purpose of the Study:
- To investigate the role of lysosomes and LMP in chronic lymphocytic leukemia (CLL).
- To evaluate the efficacy of the lysosomotropic agent siramesine in CLL cells.
- To explore the potential of targeting lysosomal pathways as a therapeutic strategy for CLL.
Main Methods:
- Treatment of CLL cells and normal B cells with siramesine.
- Assessment of LMP, lipid peroxidation, mitochondrial membrane potential, and reactive oxygen species.
- Analysis of sphingolipid metabolism, including sphingosine-1-phosphate phosphatase 1 (SPP1) expression and sphingosine levels.
- Evaluation of the effects of lipid antioxidants and protease inhibitors.
Main Results:
- CLL cells were sensitive to siramesine, which induced LMP, lipid peroxidation, and mitochondrial dysfunction.
- Siramesine was more effective in CLL cells than normal B cells, with cell death inhibited by lipid antioxidants.
- CLL cells exhibited increased lysosomes, SPP1 expression, and sphingosine levels compared to normal B cells.
- Elevated sphingosine levels enhanced LMP and cell death specifically in CLL cells.
Conclusions:
- Excess sphingosine in CLL cells contributes to their sensitivity to LMP.
- Targeting lysosomal pathways, particularly those involving sphingolipids, represents a promising therapeutic strategy for CLL.
- Siramesine demonstrates potential as a treatment for CLL by exploiting lysosomal vulnerabilities.
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