Back
Full-text
Journal article

Important role of CYP2J2 in protein kinase inhibitor degradation: a possible role in intratumor drug disposition and resistance.

  • Narjoz C Université Paris Descartes, INSERM UMR S-U775, Sorbonne Paris Cité, Paris, France; Hôpital Européen Georges Pompidou, Service de Biochimie, Unité Fonctionnelle de Pharmacogénétique et Oncologie Moléculaire, Paris, France.
  • Favre A Quantitative Mass Spectrometry Facility, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
  • McMullen J Quantitative Mass Spectrometry Facility, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
  • Kiehl P Quantitative Mass Spectrometry Facility, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
  • Montemurro M University Hospital Zürich, Oncology, Zürich, Switzerland.
  • Figg WD Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
  • Beaune P Université Paris Descartes, INSERM UMR S-U775, Sorbonne Paris Cité, Paris, France; Hôpital Européen Georges Pompidou, Service de Biochimie, Unité Fonctionnelle de Pharmacogénétique et Oncologie Moléculaire, Paris, France.
  • de Waziers I Université Paris Descartes, INSERM UMR S-U775, Sorbonne Paris Cité, Paris, France.
  • Rochat B Quantitative Mass Spectrometry Facility, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Show more…
  • 2014-05-14
Published in:
  • PloS one. - 2014
Benzamides
Carcinoma, Hepatocellular
Cell Line, Tumor
Cytochrome P-450 CYP1A1
Cytochrome P-450 CYP1B1
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System
Dasatinib
Hep G2 Cells
Humans
Imatinib Mesylate
Indoles
Liver Neoplasms
Niacinamide
Phenylurea Compounds
Piperazines
Protein Kinase Inhibitors
Pyrimidines
Pyrroles
Reverse Transcriptase Polymerase Chain Reaction
Sorafenib
Sunitinib
Thiazoles
English We have investigated in vitro the metabolic capability of 3 extrahepatic cytochromes P-450, CYP1A1, 1B1 and 2J2, known to be over-expressed in various tumors, to biotransform 5 tyrosine kinase inhibitors (TKI): dasatinib, imatinib, nilotinib, sorafenib and sunitinib. Moreover, mRNA expression of CYP1A1, 1B1, 2J2 and 3A4 in 6 hepatocellular and 14 renal cell carcinoma tumor tissues and their surrounding healthy tissues, was determined. Our results show that CYP1A1, 1B1 and especially 2J2 can rapidly biotransform the studied TKIs with a metabolic efficiency similar to that of CYP3A4. The mRNA expression of CYP1A1, 1B1, 2J2 and 3A4 in tumor biopsies has shown i) the strong variability of CYP expression and ii) distinct outliers showing high expression levels (esp. CYP2J2) that are compatible with high intratumoral CYP activity and tumor-specific TKI degradation. CYP2J2 inhibition could be a novel clinical strategy to specifically increase the intratumoral rather than plasma TKI levels, improving TKI efficacy and extending the duration before relapse. Such an approach would be akin to beta-lactamase inhibition, a classical strategy to avoid antibiotic degradation and resistance.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/298281
Statistics
Document views: 59 File downloads:
  • Full-text: 0