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Blood, 15 May 2001, Vol. 97, No. 10, pp. 3234-3243
NEOPLASIA
Tyrosine kinase inhibitor STI571 potentiates the pharmacologic
activity of retinoic acid in acute promyelocytic leukemia cells:
effects on the degradation of RAR and PML-RAR
Maurizio Gianni',
Yesim Kalaç,
Isabella Ponzanelli,
Alessandro Rambaldi,
Mineko Terao, and
Enrico Garattini
From the Divisione di Ematologia, Ospedali Riuniti di
Bergamo, Bergamo, Italy; and Laboratorio di Biologia Molecolare, Centro
Catullo e Daniela Borgomainerio, Istituto di Ricerche Farmacologiche
"Mario Negri," Milano, Italy.
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-RAR + acute promyelocytic leukemia
NB4 and the PML-RAR myeloblastic HL60 and U937 cell
lines. In addition, STI571 relieves the cyto-differentiation block
observed in the ATRA-resistant cell lines, NB4.R1, NB4.306, and
NB4.007. In NB4 promyelocytes, a RAR 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-RAR and RAR. 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.
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