Compound 48, a novel dual PPAR alpha/gamma ligand, inhibits the growth of human CML cell lines and enhances the anticancer-effects of imatinib.
Compound 48 (C48) is a novel dual ligand for peroxisome proliferator-activated receptor alpha and gamma (PPAR alpha/gamma). Culture of imatinib-sensitive and -resistant CML cell lines with C48 resulted in a strong growth inhibition which associated with G0/G1 cell cycle arrest. However, it showed no obvious toxicity to normal CD34(+) hematopoietic stem cells. Decrease of pSTATs and pAKT were noticed suggesting that interference of AKT and STATs signaling may be the mechanisms for the effects of PPAR alpha/gamma ligands. Of more clinical importance, this ligand strongly enhanced the anticancer-effects of imatinib. Overall, our data suggest that the PPAR alpha/gamma ligands may have potentials in the treatment of CML in an adjuvant setting either before or after the development of imatinib resistance.
Bertz
Janina
J
Division of Hematology/Oncology, Universitätsmedizin Berlin Charité, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany.
Zang
Chuanbing
C
Liu
Hongyu
H
Wächter
Marlies
M
Possinger
Kurt
K
Koeffler
H Phillip
HP
Elstner
Elena
E
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001578:Benzopyrans / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D047493:PPAR alpha / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D001549:Benzamides; D001578:Benzopyrans; D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate