title: Lysosomotropic agents selectively target chronic lymphocytic leukemia cells due to altered sphingolipid metabolism.
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.
authors: Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.|Research Institute of Oncology and Hematology (formerly Manitoba Institute of Cell Biology), CancerCare Manitoba, Winnipeg, Manitoba, Canada.
authors: R F
authors: RF
authors: Dielschneider
authors: Research Institute of Oncology and Hematology (formerly Manitoba Institute of Cell Biology), CancerCare Manitoba, Winnipeg, Manitoba, Canada.
authors: H
authors: H
authors: Eisenstat
authors: Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
authors: S
authors: S
authors: Mi
authors: Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
authors: J M
authors: JM
authors: Curtis
authors: Research Institute of Oncology and Hematology (formerly Manitoba Institute of Cell Biology), CancerCare Manitoba, Winnipeg, Manitoba, Canada.
authors: W
authors: W
authors: Xiao
authors: Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.|Research Institute of Oncology and Hematology (formerly Manitoba Institute of Cell Biology), CancerCare Manitoba, Winnipeg, Manitoba, Canada.
authors: J B
authors: JB
authors: Johnston
authors: Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.|Research Institute of Oncology and Hematology (formerly Manitoba Institute of Cell Biology), CancerCare Manitoba, Winnipeg, Manitoba, Canada.
authors: S B
authors: SB
authors: Gibson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D013107:Sphingolipids / Q000378:metabolism*; D013110:Sphingosine / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C109644:Lu 28-179; D008565:Membrane Proteins; D013107:Sphingolipids; D013141:Spiro Compounds; C498527:SGPP1 protein, human; D010744:Phosphoric Monoester Hydrolases; D013110:Sphingosine