sphingosine-1-phosphate and Leukemia--Myeloid--Acute

Impaired apoptotic pathways in leukemic cells enable them to grow in an uncontrolled way. Moreover, aberrations in the apoptotic pathways are the main factor of leukemic cells drug resistance.. To assess the presence of potential abnormalities that might promote dysfunction of leukemic cells growth, HPLC system was used to determine sphingosine (SFO), sphinganine (SFA), sphingosine-1-phosphate (S1P) and ceramide (CER) concentration in the blood collected from patients diagnose with acute myeloblastic leukemia (AML; n = 49) and compare to values of control (healthily) group (n = 51). Additionally, in AML group concentration of SFO, SFA, S1P and CER was determined in bone marrow plasma and compared to respective values in blood plasma. The concentration of S1P and CER binding protein - plasma gelsolin (GSN) was also assessed in collected samples using immunoblotting assay.. We observed that in AML patients the average SFO, SFA and CER concentration in blood plasma was significantly higher (p < 0.001) compare to control group, when blood plasma S1P concentration was significantly lower (p < 0.001). At the same time the CER/S1P ratio in AML patient (44.5 ± 19.4) was about 54% higher compare to control group (20.9 ± 13.1). Interestingly the average concentration of S1P in blood plasma (196 ± 13 pmol/ml) was higher compare to its concentration in plasma collected from bone marrow (154 ± 21 pmol/ml).. We hypothesize that changes in profile of sphingolipids concentration and some of their binding protein partners such as GSN in extracellular environment of blood and bone marrow cells in leukemic patients can be targeted to develop new AML treatment method(s).

Topics: Adult; Aged; Aged, 80 and over; Bone Marrow; Case-Control Studies; Ceramides; Female; Gelsolin; Humans; Leukemia, Myeloid, Acute; Lysophospholipids; Male; Middle Aged; Sphingosine

Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy and bone marrow transplantation, overall survival remains poor. Sphingosine kinase 1 (SPHK1) generates the bioactive lipid sphingosine 1-phosphate (S1P) and has established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers. The role and targeting of SPHK1 in primary AML, however, has not been previously investigated. Here we show that SPHK1 is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SPHK1 induced caspase-dependent cell death in AML cell lines, primary AML patient blasts, and isolated AML patient leukemic progenitor/stem cells, with negligible effects on normal bone marrow CD34

Topics: Amino Acid Chloromethyl Ketones; Amino Alcohols; Animals; Bone Marrow Cells; Caspase Inhibitors; Caspases; Cell Death; Cell Line, Tumor; Female; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid, Acute; Lysophospholipids; Mice; Mice, Inbred NOD; Molecular Targeted Therapy; Myeloid Cell Leukemia Sequence 1 Protein; Neoplastic Stem Cells; Phosphotransferases (Alcohol Group Acceptor); Protein Kinase Inhibitors; Quinolines; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Survival Analysis; Xenograft Model Antitumor Assays

There is an urgent unmet need for new therapeutics in acute myeloid leukemia (AML) as standard therapy has not changed in the past three decades and outcome remains poor for most patients. Sphingolipid dysregulation through decreased ceramide levels and elevated sphingosine 1-phosphate (S1P) promotes cancer cell growth and survival. Acid ceramidase (AC) catalyzes ceramide breakdown to sphingosine, the precursor for S1P. We report for the first time that AC is required for AML blast survival. Transcriptome analysis and enzymatic assay show that primary AML cells have high levels of AC expression and activity. Treatment of patient samples and cell lines with AC inhibitor LCL204 reduced viability and induced apoptosis. AC overexpression increased the expression of anti-apoptotic Mcl-1, significantly increased S1P and decreased ceramide. Conversely, LCL204 induced ceramide accumulation and decreased Mcl-1 through post-translational mechanisms. LCL204 treatment significantly increased overall survival of C57BL/6 mice engrafted with leukemic C1498 cells and significantly decreased leukemic burden in NSG mice engrafted with primary human AML cells. Collectively, these studies demonstrate that AC plays a critical role in AML survival through regulation of both sphingolipid levels and Mcl-1. We propose that AC warrants further exploration as a novel therapeutic target in AML.

Topics: Acid Ceramidase; Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Cell Survival; Ceramides; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Lysophospholipids; Mice, Inbred C57BL; Molecular Targeted Therapy; Myeloid Cell Leukemia Sequence 1 Protein; RNA Interference; Signal Transduction; Sphingosine; Time Factors; Transfection; Tumor Cells, Cultured; Up-Regulation; Xenograft Model Antitumor Assays