Peroxisome proliferator-activated receptor activation increases imatinib uptake and killing of chronic myeloid leukemia cells.

Abstract

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.

• Authors: Lihui Wang, Athina Giannoudis, Gemma Austin, Richard E Clark
• Journal: Experimental hematology (Exp Hematol) Vol. 40 Issue 10 Pg. 811-9.e2 (Oct 2012) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 22677017 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Benzamides
• Octamer Transcription Factor-1
• PPAR alpha
• PPAR gamma
• Piperazines
• Pou2f1 protein, mouse
• Pyrimidines
• Imatinib Mesylate

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology)
• Benzamides
• Female
• Gene Expression Regulation, Leukemic (drug effects)
• Hepatocytes (metabolism, pathology)
• Humans
• Imatinib Mesylate
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, metabolism, pathology)
• Liver (metabolism, pathology)
• Male
• Mice
• Octamer Transcription Factor-1 (metabolism)
• PPAR alpha (biosynthesis)
• PPAR gamma (biosynthesis)
• Piperazines (pharmacokinetics, pharmacology)
• Pyrimidines (pharmacokinetics, pharmacology)
• Up-Regulation (drug effects)