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N-(4-hydroxyphenyl)retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes

Leukemia volume 16, pages 902–910 (2002)Cite this article

Abstract

The retinoid, N-(4-hydroxyphenyl)retinamide (4-HPR), mediates p53-independent cytotoxicity and can increase reactive oxygen species and ceramide in solid tumor cell lines. We determined changes in ceramide and cytotoxicity upon treatment with 4-HPR (3–12 μM) in six human acute lymphoblastic leukemia (ALL) cell lines: T cell (MOLT-3, MOLT-4, CEM), pre-B-cell (NALM-6, SMS-SB), and null cell (NALL-1). Exposure to 4-HPR (12 μM) for 96 h caused 4.7 (MOLT-3), 3.5 (MOLT-4), 3.9 (CEM), 2.9 (NALM-6), 4.7 (SMS-SB), AND 4.5 (NALL-1) logs of cell kill. The average 4-HPR concentration that killed 99% of cells (LC99) for all six lines was 4.8 μM (range: 1.5–8.9 μM). Treatment with 4-HPR (9 μM) for 24 h resulted in an 8.9 ± 1.0-fold (range: 4.9–15.7-fold) increase of ceramide. Ceramide increase was time- and dose-dependent and abrogated by inhibitors of de novo ceramide synthesis. Concurrent inhibition of ceramide glycosylation/acylation by d,l-threo-(1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol) (PPMP) further increased ceramide levels, and synergistically increased 4-HPR cytotoxicity in four of six ALL cell lines. 4-HPR was minimally cytotoxic to peripheral blood mononuclear cells and a lymphoblastoid cell line, and increased ceramide <2-fold. Thus, 4-HPR was cytotoxic and increased ceramide in ALL cell lines, but not in non-malignant lymphoid cell types.

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Acknowledgements

Supported in part by grants from the Neil Bogart Memorial Laboratories of the TJ Martell Foundation for Leukemia, Cancer and AIDS Research (BM, CR); The Wright Foundation (BM); The Stop Cancer Foundation (BM); The Colvin Leukemia Fund (BM); The Cusumano Leukemia Fund of the Michael Hoefflin Foundation (BM), by Public Health Service grant CA81403 (CR) from the National Cancer Institute (NCI), National Institutes of Health, Department of Health and Human Services; and a Howard Hughes Medical Institute Medical Student Research Training Fellowship (PO).

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  1. Division of Hematology-Oncology, Childrens Hospital, Los Angeles, CA, USA

    PH O'Donnell, W-X Guo, CP Reynolds & BJ Maurer

  2. Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA, USA

    CP Reynolds & BJ Maurer

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O'Donnell, P., Guo, WX., Reynolds, C. et al. N-(4-hydroxyphenyl)retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes. Leukemia 16, 902–910 (2002). https://doi.org/10.1038/sj.leu.2402485

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