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Synthetic triterpenoids activate a pathway for apoptosis in AML cells involving downregulation of FLIP and sensitization to TRAIL

Leukemia volume 17, pages 2122–2129 (2003)Cite this article

Abstract

Acute myelogenous leukemia (AML) remains a deadly disease for most adult patients, due primarily to the emergence of chemoresistant cells. Defects in apoptosis pathways make important contributions to chemoresistance, suggesting a need to restore apoptosis sensitivity or to identify alternative pathways for apoptosis induction. Triterpenoids represent a class of naturally occurring and synthetic compounds with demonstrated antitumor activity, including 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its methyl ester (CDDO-m). We explored the effects of CDDO and CDDO-m in vitro on established AML cell lines (HL-60, U937, AML-2) and on freshly isolated AML blasts. CDDO and CDDO-m reduced the viability of all AML cell lines tested in a dose-dependent manner, with effective doses for killing 50% of cells (ED50) within 48 h of ∼1 and 0.5 μ M, respectively. CDDO or CDDO-m also induced substantial increases in cell death in five out of 10 samples of primary AML blasts. Cell death induced by CDDO and CDDO-m was attributed to apoptosis, based on characteristic cell morphology and evidence of caspase activation. Immunoblot analysis demonstrated proteolytic processing of caspase-3, -7, and -8, but not caspase-9, suggesting the involvement of the ‘extrinsic’ pathway, linked to apoptosis induction by TNF-family death receptors. Accordingly, CDDO and CDDO-m induced concentration-dependent reductions in the levels of FLIP protein, an endogenous antagonist of caspase-8, without altering the levels of several other apoptosis-relevant proteins. Reductions in FLIP were rapid, detectable within 3 h after exposure of AML cell lines to CDDO or CDDO-m. CDDO and CDDO-m also sensitized two of four leukemia lines to TRAIL, a TNF-family death ligand. The findings suggest that synthetic triterpenoids warrant further investigation in the treatment of AML, alone or in combination with TRAIL or other immune-based therapies.

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Authors and Affiliations

  1. The Burnham Institute, La Jolla, CA, USA

    W-S Suh, Y S Kim, A D Schimmer, S Kitada & J C Reed

  2. Princess Margaret Hospital, Toronto, Canada, Ont.

    M Minden

  3. MD Anderson Cancer Cntr, Houston, TX, USA

    M Andreeff

  4. Dartmouth Medical School, Hanover, NH, USA

    N Suh & M Sporn

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Suh, WS., Kim, Y., Schimmer, A. et al. Synthetic triterpenoids activate a pathway for apoptosis in AML cells involving downregulation of FLIP and sensitization to TRAIL. Leukemia 17, 2122–2129 (2003). https://doi.org/10.1038/sj.leu.2403112

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