The novel triterpenoid CDDO-Me suppresses MAPK pathways and promotes p38 activation in acute myeloid leukemia cells

Leukemia. 2005 Aug;19(8):1350-4. doi: 10.1038/sj.leu.2403828.

Abstract

Development of novel therapeutic strategies is a continuing challenge for the treatment of acute myeloid leukemia (AML). The novel triterpenoid, C-28 methyl ester of 2-cyano-3,12-dioxoolen-1,9-dien-28-oic acid (CDDO-Me), induces apoptosis in myeloid leukemic cell lines and in primary AML samples. In this report, the effects of CDDO-Me on CD34(+) AML progenitor cells in vitro were examined. CDDO-Me induced apoptosis in all but one of ten AML samples. CDDO-Me is known to inhibit the activation of ERK1/2. In this series of primary AML samples, ERK was expressed and phosphorylated in all patient samples studied and CDDO-Me inhibited ERK phosphorylation in five of 10 samples. However, CDDO-Me induced apoptosis in four of five samples without decreasing pERK levels, suggesting that pERK is not the sole target of the compound. CDDO-Me induced phosphorylation of p38 in AML-derived U937 cells. Pretreatment of U937 cells with a p38 inhibitor protected cells from the cyto-toxic effects of CDDO-Me. These findings suggest a role for p38 in CDDO-Me-induced apoptosis. In preliminary studies, CDDO-Me induced p38 phosphorylation in seven of eight primary AML samples. These findings suggest that CDDO-Me treatment shifts cell signaling away from cyto-protective pathways and thus CDDO-Me may be effective for the treatment of AML.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Disease
  • Apoptosis / drug effects
  • Humans
  • Leukemia, Myeloid / drug therapy*
  • Leukemia, Myeloid / pathology
  • MAP Kinase Signaling System / drug effects*
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology
  • Oleanolic Acid / analogs & derivatives*
  • Oleanolic Acid / pharmacology
  • Phosphorylation / drug effects
  • Triterpenes / pharmacology
  • Tumor Cells, Cultured
  • p38 Mitogen-Activated Protein Kinases / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Triterpenes
  • Oleanolic Acid
  • methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate
  • p38 Mitogen-Activated Protein Kinases