ArticleJournal of lipid research2019
Chemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergetics in resistant HL-60 cells.
Article in Journal of lipid research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 39 citations in OpenAlex.
- Re-evaluating the rationale for targeting oxidative phosphorylation in acute myeloid leukemia.The Biochemical journal · 2026Review
- Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia.Blood neoplasia · 2026Article
- ASAH1-mediated sphingolipid metabolic reprogramming in venetoclax resistance of AML: beyond the monocytic phenotypes.BMC cancer · 2025Article
- Identification of Lipid Species Signatures in FOLFOXIRI-Resistant Colorectal Cancer Cells.International journal of molecular sciences · 2025Article
- The role and therapeutic potential of glucose metabolism in multidrug resistance of cancer.Frontiers in cell and developmental biology · 2025Review
- The Drug Transporter P-Glycoprotein and Its Impact on Ceramide Metabolism-An Unconventional Ally in Cancer Treatment.International journal of molecular sciences · 2024Review
- Mitochondrial abnormalities as a target of intervention in acute myeloid leukemia.Frontiers in oncology · 2024Review
- Influences on the Hematopoietic Stem Cell Niche.SciBase hematology & blood disorders · 2024Article
- Article
- Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.Cancers · 2023Article
- Metabolomic profile of acute myeloid leukaemia parallels of prognosis and response to therapy.Scientific reports · 2023Article
- Article
- Targeting metabolic vulnerabilities to overcome resistance to therapy in acute myeloid leukemia.Cancer drug resistance (Alhambra, Calif.) · 2023Review
- Review
- Potential role of autophagy induced by FLT3-ITD and acid ceramidase in acute myeloid leukemia chemo-resistance: new insights.Cell communication and signaling : CCS · 2022Review
- Advancements on the Multifaceted Roles of Sphingolipids in Hematological Malignancies.International journal of molecular sciences · 2022Review
- Ceramide nanoliposomes augment the efficacy of venetoclax and cytarabine in models of acute myeloid leukemia.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Harnessing the power of sphingolipids: Prospects for acute myeloid leukemia.Blood reviews · 2022Review
- Review
- Alterations in sphingolipid composition and mitochondrial bioenergetics represent synergistic therapeutic vulnerabilities linked to multidrug resistance in leukemia.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
Corrections and comments
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Authors and funding
17 authors at 7 institutions in 3 countries.
Funding
Abstract
The combination of daunorubicin (dnr) and cytarabine (Ara-C) is a cornerstone of treatment for acute myelogenous leukemia (AML); resistance to these drugs is a major cause of treatment failure. Ceramide, a sphingolipid (SL), plays a critical role in cancer cell apoptosis in response to chemotherapy. Here, we investigated the effects of chemotherapy selection pressure with Ara-C and dnr on SL composition and enzyme activity in the AML cell line HL-60. Resistant cells, those selected for growth in Ara-C- and dnr-containing medium (HL-60/Ara-C and HL-60/dnr, respectively), demonstrated upregulated expression and activity of glucosylceramide synthase, acid ceramidase (AC), and sphingosine kinase 1 (SPHK1); were more resistant to ceramide than parental cells; and displayed sensitivity to inhibitors of SL metabolism. Lipidomic analysis revealed a general ceramide deficit and a profound upswing in levels of sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) in HL-60/dnr cells versus parental and HL-60/Ara-C cells. Both chemotherapy-selected cells also exhibited comprehensive upregulations in mitochondrial biogenesis consistent with heightened reliance on oxidative phosphorylation, a property that was partially reversed by exposure to AC and SPHK1 inhibitors and that supports a role for the phosphorylation system in resistance. In summary, dnr and Ara-C selection pressure induces acute reductions in ceramide levels and large increases in S1P and C1P, concomitant with cell resilience bolstered by enhanced mitochondrial remodeling. Thus, strategic control of ceramide metabolism and further research to define mitochondrial perturbations that accompany the drug-resistant phenotype offer new opportunities for developing therapies that regulate cancer growth.
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