title: Dual PPARalpha/gamma ligand TZD18 either alone or in combination with imatinib inhibits proliferation and induces apoptosis of human CML cell lines.
abstract: Despite progress in the treatment of early-stage chronic myeloid leukemia (CML), the accelerated and blastic phases of CML still remain a therapeutic challenge. Persistence of BCR-ABL-positive (bcr-abl(+)) cells or secondary resistance during imatinib therapy frequently occurs. In this study, we investigated the activity of a novel dual ligand specific for peroxisome proliferator-activated receptor alpha and gamma (PPARalpha/gamma) against CML blast crisis cell lines. Exposure of these cell lines (K562, KU812 and KCL22) to TZD18 resulted in a growth inhibition in a dose- and time-dependent manner. This effect may not be mediated through PPARgamma and PPARalpha activation, since antagonists of PPARgamma and/or PPARalpha could not reverse this inhibition. Western blotting analysis showed that expression of the cyclin dependent kinase inhibitor (CDKI) p27(kip1) was enhanced, whereas levels of cyclin E, cyclin D2 and cyclin dependent kinase 2 (CDK-2) were decreased when these cells were treated with TZD18. Most interestingly, TZD18 synergistically enhanced the antiproliferative and pro-apoptotic effect of imatinib. Overall, our findings strongly suggest that either TZD18, either alone or in combination with imatinib may be beneficial for the treatment of CML in myeloid blast crisis.
authors.affiliation: Division of Oncology/Hematology, Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany.
authors.forename: Chuanbing
authors.initials: C
authors.lastname: Zang
authors.forename: Hongyu
authors.initials: H
authors.lastname: Liu
authors.forename: Marlies
authors.initials: M
authors.lastname: Waechter
authors.forename: Jan
authors.initials: J
authors.lastname: Eucker
authors.forename: Janina
authors.initials: J
authors.lastname: Bertz
authors.forename: Kurt
authors.initials: K
authors.lastname: Possinger
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.forename: Elena
authors.initials: E
authors.lastname: Elstner
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D047493:PPAR alpha / Q000819:agonists; D047495:PPAR gamma / Q000819:agonists; D010647:Phenyl Ethers / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: C483680:5-(3-(3-(4-phenoxy-2-propylphenoxy)propoxy)phenyl)-2,4-thiazolidinedione; D001549:Benzamides; D047493:PPAR alpha; D047495:PPAR gamma; D010647:Phenyl Ethers; D010879:Piperazines; D011743:Pyrimidines; D045162:Thiazolidinediones; D000068877:Imatinib Mesylate