The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines Academic Article uri icon

Overview

MeSH Major

  • Farnesyltranstransferase
  • P-Glycoprotein
  • Quinolones

abstract

  • Farnesyl transferase inhibitors (FTIs) target signal-transduction pathways responsible for the proliferation and survival of hematologic malignancies, including acute myelogenous leukemias (AML). Lonafarnib has been shown to be a potent inhibitor of Pgp-mediated drug efflux. On the basis of these findings, we examined the Pgp-inhibitory properties of tipifarnib and assessed its activity when combined with anthracyclines. The effects of tipifarnib on cell proliferation, induction of apoptosis and inhibition of Pgp-mediated anthracycline efflux were analyzed in two human leukemia cell lines overexpressing Pgp (CCRF-CEM and KG1a). Measurement of residual daunorubicin (DNR)-mediated fluorescence after incubation with DNR and tipifarnib demonstrated that tipifarnib significantly inhibited DNR efflux in CCRF-CEM with an IC(50) value less than 0.5 microM. Proliferation and apoptosis assays after exposure to DNR in the presence or absence of tipifarnib demonstrated synergistic inhibition of cellular proliferation, and induction of apoptosis with the combination of tipifarnib and DNR. Similar data was obtained with an enantiomer of tipifarnib that possesses no FTI activity. Incubation with tipifarnib and DNR did not interfere with inhibition of the post-translational processing of HDJ-2. These data suggest that tipifarnib possesses Pgp-inhibitory activity in addition to its FTI activity. In high risk and refractory patients these properties may be exploited as a dual targeting mechanism in the therapy of AML.

publication date

  • April 2007

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1038/sj.leu.2404539

PubMed ID

  • 17268526

Additional Document Info

start page

  • 739

end page

  • 46

volume

  • 21

number

  • 4