TY - JOUR
T1 - Peroxisome proliferator-activated receptor and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias
AU - Konopleva, Marina
AU - Elstner, Elena
AU - McQueen, Teresa J.
AU - Tsao, Twee
AU - Sudarikov, Andrey
AU - Hu, Wei
AU - Schober, Wendy D.
AU - Wang, Rui Yu
AU - Chism, David
AU - Kornblau, Steven M.
AU - Younes, Anas
AU - Collins, Steven J.
AU - Koeffler, H. Phillip
AU - Andreeff, Michael
PY - 2004/10
Y1 - 2004/10
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=7444239080&partnerID=8YFLogxK
M3 - Article
C2 - 15486192
AN - SCOPUS:7444239080
SN - 1535-7163
VL - 3
SP - 1249
EP - 1262
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 10
ER -