CDDO induces apoptosis via the intrinsic pathway in lymphoid cells

S. Inoue, R. T. Snowden, M. J.S. Dyer, G. M. Cohen

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)

Abstract

The peroxisome-proliferator-activated receptor (PPAR) γ 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.

Original languageEnglish
Pages (from-to)948-952
Number of pages5
JournalLeukemia
Volume18
Issue number5
DOIs
Publication statusPublished - 2004 May
Externally publishedYes

Keywords

  • Apoptosis
  • CDDO
  • Chronic lymphocytic leukemia (CLL)
  • Intrinsic pathway

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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