Peroxisome proliferator-activated receptor activation increases imatinib uptake and killing of chronic myeloid leukemia cells.
Low pretreatment expression of the imatinib uptake transporter human organic cation transporter 1 (hOCT1) is associated with inferior complete cytogenetic response rates, progression-free survival, and overall survival in imatinib-treated chronic myeloid leukemia (CML). Upregulation of hOCT1 can therefore increase the uptake of imatinib. The hOCT1 gene is transactivated by hepatocyte nuclear factor 4α in human liver, and peroxisome proliferator-activated receptors (PPAR) α and γ activation increases OCT1 expression in mouse hepatocytes. Here we report that no isoform of hepatocyte nuclear factor 4α is expressed in CML lines or in CML primary cells. In contrast, both PPARα and γ were expressed in all CML cell lines and primary cells studied. PPARα agonist treatment increased imatinib killing of CML KCL22 cells and primitive CD34(+) cells, and also upregulates hOCT1 gene expression and increases imatinib uptake into KCL22 cells and primary cells. PPARα agonists might potentially be of clinical use in CML patients failing imatinib.
Section of Haematology, Department of Molecular and Cancer Medicine, the University of Liverpool, Liverpool, UK.
Lihui
L
Wang
Athina
A
Giannoudis
Gemma
G
Austin
Richard E
RE
Clark
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001549:Benzamides; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D050811:Octamer Transcription Factor-1 / Q000378:metabolism; D047493:PPAR alpha / Q000096:biosynthesis*; D047495:PPAR gamma / Q000096:biosynthesis*; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D001549:Benzamides; D050811:Octamer Transcription Factor-1; D047493:PPAR alpha; D047495:PPAR gamma; D010879:Piperazines; C494166:Pou2f1 protein, mouse; D011743:Pyrimidines; D000068877:Imatinib Mesylate