Tyrosine kinase inhibitor ST1571 potentiates the pharmacologic activity ofretinoic acid in acute promyelocytic leukemia cells: effects on the degradation of RAR alpha and PML-RAR alpha

The 2-phenylaminopyrimidine derivative STI571 is a selective inhibitor of c -Abl, c-kit, and platelet-derived growth factor-receptor tyrosine kinases a nd is presently in phase II-III clinical studies. Here, this study reports on a novel pharmacologic activity of the compound, ie, enhancement of the c yto-differentiating, growth-inhibitory, and apoptogenic, actions of all-tra ns-retinoic acid (ATRA). Whereas STI571 is not a cytodifferentiating agent by itself, the compound interacts with ATRA and enhances the myeloid matura tion program set in motion by the retinoid in the PML-RAR alpha (+) acute p romyelocytic leukemia NB4 and the PML-RAR alpha (-) myeloblastic HL60 and U 937 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 RAR alpha agonist, but not an RXR agonist, can substi tute 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 in creased up-regulation of the expression of a number of genes coding for mye loid differentiation markers, including CD11b, CD11c, and some of the compo nents of the nicotinamide adenine dinucleotide phosphate-oxidase enzymatic complex. All this is accompanied by inhibition of c-Abl tyrosine phosphoryl ation and retardation of the retinoid-dependent degradation of PML-RAR alph a and RAR alpha. 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. (Blood. 2001;97 :3234-3243) (C) 2001 by The American Society of Hematology.