Tyrosine kinase inhibitor STI571 potentiates the pharmacologic activity of retinoic acid in acute promyelocytic leukemia cells: Effects on the degradation of RARα and PML-RARα

Maurizio Gianni', Yesim Kalaç, Isabella Ponzanelli, Alessandro Rambaldi, Mineko Terao, Enrico Garattini

Research output: Contribution to journalArticle

Abstract

The 2-phenylaminopyrimidine derivative STI571 is a selective inhibitor of c-Abl, c-kit, and platelet-derived growth factor-receptor tyrosine kinases and is presently in phase II-III clinical studies. Here, this study reports on a novel pharmacologic activity of the compound, ie, enhancement of the cyto-differentiating, growth-inhibitory, and apoptogenic actions of all-trans-retinoic acid (ATRA). Whereas STI571 is not a cytodifferentiating agent by itself, the compound interacts with ATRA and enhances the myeloid maturation program set in motion by the retinoid in the PML-RARα+ acute promyelocytic leukemia NB4 and the PML-RARα- myeloblastic HL60 and U937 cell lines. In addition, STI571 relieves the cytodifferentiation block observed in the ATRA-resistant cell lines, NB4.R1, NB4.306, and NB4.007. In NB4 promyelocytes, a RARα agonist, but not an RXR agonist, can substitute for ATRA and interact with STI571. By contrast, STI571 is unique among c-Abl-specific tyrosine kinase inhibitors in modulating the pharmacologic activity of ATRA. In NB4 cells, enhanced cyto-differentiation results in increased up-regulation of the expression of a number of genes coding for myeloid differentiation markers, including CD11b, CD11c, and some of the components of the nicotinamide adenine dinucleotide phosphate-oxidase enzymatic complex. All this is accompanied by inhibition of c-Abl tyrosine phosphorylation and retardation of the retinoid-dependent degradation of PML-RARα and RARα. Stabilization of the 2 retinoic acid receptors is likely to be the result of augmented and accelerated inhibition of the proteasome-dependent proteolytic activity observed on ATRA treatment.

Original languageEnglish
Pages (from-to)3234-3243
Number of pages10
JournalBlood
Volume97
Issue number10
DOIs
Publication statusPublished - May 15 2001

ASJC Scopus subject areas

  • Hematology

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