ArticleLeukemia research2015
Dynamics of ceramide generation and metabolism in response to fenretinide--Diversity within and among leukemia.
Article in Leukemia research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
13 citing papers in PubMed, 20 citations in OpenAlex.
- High-throughput in vitro drug screening and in vivo studies identify fenretinide as a brain-penetrant DMG therapeutic.Neuro-oncology · 2025Article
- Drug Resistance: The Role of Sphingolipid Metabolism.International journal of molecular sciences · 2025Review
- Diagnostic and Therapeutic Implications of the SUMOylation Pathway in Acute Myeloid Leukemia.Cancers · 2025Review
- Nano-fenretinide demonstrates remarkable activity in acute promyeloid leukemia cells.Scientific reports · 2024Article
- A genome-wide CRISPR screen implicates plasma membrane asymmetry in exogenous C6-ceramide toxicity.Biology open · 2022Article
- Advancements on the Multifaceted Roles of Sphingolipids in Hematological Malignancies.International journal of molecular sciences · 2022Review
- Harnessing the power of sphingolipids: Prospects for acute myeloid leukemia.Blood reviews · 2022Review
- Targeting Sphingolipids for Cancer Therapy.Frontiers in oncology · 2021Review
- Fenretinide binding to the lysosomal protein saposin D alters ceramide solubilization and hydrolysis.RSC medicinal chemistry · 2020Article
- Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities.Advances in experimental medicine and biology · 2020Review
- The SUMO Pathway in Hematomalignancies and Their Response to Therapies.International journal of molecular sciences · 2019Review
- Fenretinide-induced Apoptosis of Acute Myeloid Leukemia Cells via NR4A1 Translocation into Mitochondria and Bcl-2 Transformation.Journal of Cancer · 2019Article
- The emergence of acid ceramidase as a therapeutic target for acute myeloid leukemia.Expert opinion on therapeutic targets · 2017Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
Fenretinide, N-(4-hydroxyphenyl)retinamide, (4-HPR), a synthetic retinoid, owes its cancer-toxic effects in part to the generation of ceramide, a potent tumor-suppressing sphingolipid. As such, 4-HPR has garnered considerable interest as a chemotherapeutic. Cancer cells, however, via various metabolic routes, inactivate ceramide, and this can limit 4-HPR efficacy. As relatively little is known regarding 4-HPR-induced ceramide management in acute myelogeneous leukemia (AML), we undertook the present study to evaluate the impact of 4-HPR on ceramide production, metabolism, and cytotoxicity. In KG-1, HL-60, and HL-60/VCR (multidrug resistant) human leukemia cells, 4-HPR induced 15-, 2-, and 20-fold increases in ceramide (measured using [3H]palmitic acid), respectively. By use of specific inhibitors we show that ceramide was produced by sphingomyelinase and de novo pathways in response to 4-HPR exposure. HL-60/VCR cells metabolized ceramide to glucosylceramide (GC). 4-HPR exposure (1.25-10 μM) reduced viability in all cell lines, with approximate IC50's ranging from 1 to 8.0 μM. Reactive oxygen species (ROS) were generated in response to 4-HPR treatment, and the concomitant cytotoxicity was reversed by addition of vitamin E. 4-HPR was not cytotoxic nor did it elicit ceramide formation in K562, a chronic myeloid leukemia cell line; however, K562 cells were sensitive to a cell-deliverable form of ceramide, C6-ceramide. Treatment of Molt-3, an acute lymphoblastic leukemia cell line, with 4-HPR revealed moderate ceramide production (5-fold over control), robust conversion of ceramide to GC and sphingomyelin, and resistance to 4-HPR and C6-ceramide. In conclusion, this work demonstrates diversity within and among leukemia in 4-HPR sensitivity and ceramide generation and subsequent metabolism. As such, knowledge of these metabolic pathways can provide guidance for enhancing ceramide-driven effects of 4-HPR in treatment of leukemia.
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