Thiazolidinedione induces apoptosis and monocytic differentiation in the promyelocytic leukemia cell line HL60.
Thiazolidinedione (TZD) is known to be a potent activator of peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor that constitutes a heterodimer with retinoid X receptor (RXR). Since a considerable amount of PPARgamma is expressed in various hematopoietic cells, the present study was undertaken to examine the effect of TZD in the absence or presence of LG100268, an RXR-selective ligand, on a cultured promyelocytic leukemia cell line, HL60. Treatment with TZD (25-50 microM troglitazone or pioglitazone) markedly suppressed cell proliferation of HL60. A cell cycle analysis revealed that the suppressive effect of troglitazone on HL60 cell proliferations was caused by G0/G1 cell cycle arrest as well as by an apoptotic effect. Treatment with the same concentration of troglitazone also induced the monocytic differentiation of HL60 cells. The apoptotic or the differentiating effect of TZD on HL60 cells was synergistically enhanced by the combined treatment with 1 microM LG100268, while LG100268 alone neither had an apoptotic nor a differentiating effect on HL60 cells. These results suggest that these actions are mediated through the nuclear receptor system constituted by the PPARgamma: RXR heterodimer.
Hirase
N
N
Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Yanase
T
T
Mu
Y
Y
Muta
K
K
Umemura
T
T
Takayanagi
R
R
Nawata
H
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells / Q000187:drug effects*; D006801:Humans; D009000:Monocytes / Q000187:drug effects*; D009539:Nicotinic Acids / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
D000970:Antineoplastic Agents; D002839:Chromans; D009539:Nicotinic Acids; D011518:Proto-Oncogene Proteins; D013764:Tetrahydronaphthalenes; D013844:Thiazoles; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione; D000077288:Troglitazone; C095104:LG 100268