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- Title
Synthetic triterpenoids activate a pathway for apoptosis in AML cells involving downregulation of FLIP and sensitization to TRAIL.
- Authors
Suh, W-S.; Kim, Y. S.; Schimmer, A. D.; Kitada, S.; Minden, M.; Andreeff, M.; Suh, N.; Sporn, M.; Reed, J. C.
- 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?µM, 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.Leukemia (2003) 17, 2122-2129. doi:10.1038/sj.leu.2403112 Published online 21 August 2003
- Subjects
ACUTE myeloid leukemia; APOPTOSIS; CELL lines; MORPHOLOGY; IMMUNOBLOTTING; PROTEOLYSIS; PROTEINS
- Publication
Leukemia (08876924), 2003, Vol 17, Issue 11, p2122
- ISSN
0887-6924
- Publication type
journal article
- DOI
10.1038/sj.leu.2403112