CDDO Induces Apoptosis via the Intrinsic Pathway in Lymphoid Cells

Leukemia. 2004 May;18(5):948-52. doi: 10.1038/sj.leu.2403328.

Abstract

The peroxisome-proliferator-activated receptor (PPAR) gamma agonist, CDDO, is under investigation for use in various malignancies. The mechanisms by which CDDO induces apoptosis are controversial. We have therefore sought to determine these mechanisms using primary chronic lymphocyte leukemic (CLL) cells and Jurkat cell lines with defined apoptotic abnormalities. In these cells, CDDO induced-apoptosis involved caspase-independent loss in mitochondrial membrane potential followed by caspase processing. The pattern of CDDO-induced caspase processing, defined by use of a caspase inhibitor, strongly suggested that caspase-9 was the apical caspase. Moreover, CDDO induced apoptosis in caspase-8 and FADD-deficient but not in Bcl-xL overexpressing Jurkat cells. In CLL cells, CDDO induced an early release of mitochondrial cytochrome c and Smac that preceded apoptosis. Thus, in both cell types, CDDO induced apoptosis primarily by the intrinsic pathway with caspase-9 as the apical caspase. This has important implications in the design of novel agents for the treatment of CLL and other malignancies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Caspase 9
  • Caspases / physiology
  • Humans
  • Jurkat Cells
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Leupeptins / pharmacology
  • Oleanolic Acid / analogs & derivatives*
  • Oleanolic Acid / pharmacology*

Substances

  • 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
  • Leupeptins
  • Oleanolic Acid
  • CASP9 protein, human
  • Caspase 9
  • Caspases
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde