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Synthetic triterpenoids have cytotoxicity in pediatric acute lymphoblastic leukemia cell lines but cytotoxicity is independent of induced ceramide increase in MOLT-4 cells

Leukemia volume 22, pages 1258–1262 (2008)Cite this article

2-Cyano-3,12-dioxooleana-1,9-diene-28-oic acid (CDDO) and its derivatives, methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate (CDDO-Me) and 2-cyano-3,12-dioxooleana-1,9-diene-28-imidazolide (CDDO-Im), are synthetic triterpenoids with antitumorigenic properties in vitro and in vivo.1, 2 CDDO has been reported to decrease the activity of Her2 kinase, disrupt microtubules, induce loss of the inner mitochondrial potential and induce both caspase-dependent and caspase-independent cell death. All three compounds have increased reactive oxygen species (ROS) in various cancer cell lines. CDDO-Me suppressed nuclear factor κB (NF-κB) activity and the mitogen-activated protein kinase pathway, ERK1/2, while activating c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinases. This latter activation pattern has been observed in association with ceramide-related stress and cell death in various systems. This study concerns the cytotoxicity of CDDO, CDDO-Me and CDDO-Im in an expanded panel of pediatric acute lymphoblastic leukemia (ALL) cell lines. We report that these triterpenoids increased desaturated ceramides in ALL cells predominantly via de novo synthesis, but in a manner not clearly associated with cytotoxicity. Finally, we report that combining CDDO-Im with the cytotoxic retinoid, fenretinide (4-HPR), enhanced 4-HPR-stimulated increase of saturated ceramides (dihydroceramides) and synergized cytotoxicity. These observations suggest that combining CDDO-related triterpenoids with fenretinide resulted in a novel biochemical cellular response worth further preclinical evaluation for the treatment of pediatric ALL.

Because CDDO, CDDO-Me and CDDO-Im have been reported to activate caspases variably in cancer cell lines, caspase activation was examined in the MOLT-4 cells exposed for 2, 6 and 8 h to approximately equally cytotoxic (∼LC99) concentrations of drug (CDDO, 5 μM; CDDO-Me, 1 μM; CDDO-Im, 0.4 μM). Caspase-3 activation was observed with CDDO-Me >CDDO-Im at +6 h. Activation of caspase-3, -8 and -9 was observed with all three drugs at +8 h, with activation in CDDO-Me and CDDO-Im >CDDO.

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Acknowledgements

Supported in part by grants from The USC-CHLA Institute for Pediatric Clinical Research, The Neil Bogart Memorial Laboratories of the TJ Martell Foundation for Leukemia, Cancer and AIDS Research; The Cusumano Leukemia Fund of the Michael Hoefflin Foundation; The Tyler's Team Leukemia Fund by Public Health Service RO1 Grants CA100895, CA030715 and CA89346, and Specialized Program of Research Excellence (SPORE) Grant CA100632 from the National Cancer Institute (NCI), National Institutes of Health, Department of Health and Human Services.

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Authors and Affiliations

  1. USC-CHLA Institute for Pediatric Clinical Research, Childrens Hospital Los Angeles, Los Angeles, CA, USA

    G Kong, D Wang, H Wang, J Wu & B J Maurer

  2. Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Lipidomics Core, Medical University of South Carolina, Charleston, SC, USA

    J Bielawski

  3. Department of Blood and Marrow Transplantation, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M Konopleva & M Andreeff

  4. Division of Cell Signaling, Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, USA

    P P Ruvolo

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

    B J Maurer

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  1. G Kong
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Correspondence to B J Maurer.

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Kong, G., Wang, D., Wang, H. et al. Synthetic triterpenoids have cytotoxicity in pediatric acute lymphoblastic leukemia cell lines but cytotoxicity is independent of induced ceramide increase in MOLT-4 cells. Leukemia 22, 1258–1262 (2008). https://doi.org/10.1038/sj.leu.2405023

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