Troglitazone inhibits cell growth and induces apoptosis of B-cell acute lymphoblastic leukemia cells with t(14;18).
Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear receptor superfamily, has been detected in several human leukemia cells. Recent studies reported that PPARgamma ligands inhibit cell proliferation and induce apoptosis in both normal and malignant B-lineage cells. We investigated the expression of PPARgamma and the effects of PPARgamma ligands on UTree-O2, Bay91 and 380, three B-cell acute lymphoblastic leukemia (B-ALL) cell lines with t(14;18), which show a poor prognosis, accompanying c-myc abnormality. Western blot analysis identified expression of PPARgamma protein and real-time PCR that of PPARgamma mRNA on the three cell lines. Troglitazone (TGZ), a synthetic PPARgamma ligand, inhibited cell growth in these cell lines in a dose-dependent manner, which was associated with G(1) cell cycle arrest and apoptosis. We also found this effect PPARgamma independent since PPARgamma antagonists failed to reverse this effect. We assessed the expression of c-myc, an apoptosis-regulatory gene, since c-myc abnormality was detected in most B-ALL cells with t(14;18). TGZ was found to dose-dependently downregulate the expression of c-myc mRNA and c-myc protein in the three cell lines. These results suggest that TGZ inhibits cell growth via induction of G(1) cell cycle arrest and apoptosis in these cell lines and that TGZ-induced apoptosis, at least in part, may be related to the downregulation of c-myc expression. Moreover, the downregulation of c-myc expression by TGZ may depend on a PPARgamma-independent mechanism. Further studies indicate that PPARgamma ligands may serve as a therapeutic agent in B-ALL with t(14;18).
Takenokuchi
M
M
Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan.
Saigo
K
K
Nakamachi
Y
Y
Kawano
S
S
Hashimoto
M
M
Fujioka
T
T
Koizumi
T
T
Tatsumi
E
E
Kumagai
S
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology* / Q000627:therapeutic use; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008297:Male; D047495:PPAR gamma / Q000819:agonists / Q000096:biosynthesis*; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D014178:Translocation, Genetic / Q000235:genetics; D000077288:Troglitazone
D000970:Antineoplastic Agents; D002839:Chromans; D008024:Ligands; C489427:MYC protein, human; D047495:PPAR gamma; D016271:Proto-Oncogene Proteins c-myc; D045162:Thiazolidinediones; D000077288:Troglitazone