Peroxisome proliferator-activated receptor and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias

Marina Konopleva, Elena Elstner, Teresa J. McQueen, Twee Tsao, Andrey Sudarikov, Wei Hu, Wendy D. Schober, Rui Yu Wang, David Chism, Steven M. Kornblau, Anas Younes, Steven J. Collins, H. Phillip Koeffler, Michael Andreeff

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

The peroxisome proliferator-activated receptor γ (PPAR-γ) is a member of the nuclear receptor family that forms heterodimers with retinoid X receptor. These heterodimers bind to DNA and activate the transcription of target genes. Here, we report that the PPAR-γ receptor protein is expressed in primary myeloid and lymphoid leukemias and in lymphoma and myeloma cell lines. In this study, we compared the activity of several PPARγ ligands including BRL49653 (rosiglitazone), 15-deoxy-Δ12,14-prostaglandin J2, and the novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid on leukemia cells. Exposure to these PPAR-γ ligands induced apoptosis in myeloid (U937 and HL-60) and lymphoid (Su-DHL, Sup-M2, Ramos, Raji, Hodgkin's cell lines, and primary chronic lymphocytic leukemia) cells. A similar exposure to these PPARγ ligands induced the differentiation of myeloid leukemic cells. A combination of PPARγ ligands with a retinoid X receptor agonist (i.e., LG 100268) or a retinoic acid receptor agonist (i.e., all trans-retinoic acid) enhanced differentiating and growth-inhibitory effects. 2-Cyano-3.12-dioxooleana-1,9-dien-28-oic acid induced differentiation and apoptosis with much greater potency than the other PPARγ ligands in established cell lines and primary chronic lymphocytic leukemia samples. Exposure to 2-cyano-3, 12-dioxo-oleana-1,9-dien-28-oic acid induced mitochondrial depolarization and caspase activation, which was associated with apoptosis induction. In Bcl-2-overexpressing chronic lymphocytic leukemia cells, the small-molecule Bcl-2 inhibitor HA14-1 sensitized these cells to 2-cyano-3, 12-dioxooleana-1,9-dien-28-oic acid-induced apoptosis. These results suggest that PPARγ ligation alone and in combination with retinoids holds promise as novel therapy for leukemias by activating the transcriptional activity of target genes that control apoptosis and differentiation in leukemias.

Original languageEnglish
Pages (from-to)1249-1262
Number of pages14
JournalMolecular Cancer Therapeutics
Volume3
Issue number10
StatePublished - Oct 2004
Externally publishedYes

Fingerprint

Dive into the research topics of 'Peroxisome proliferator-activated receptor and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias'. Together they form a unique fingerprint.

Cite this