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Experimental Therapeutics |
Institut National de la Santé et de la Recherche Médicale (INSERM U496), Institut Universitaire d’Hématologie (Université Paris 7), Hôpital Saint-Louis (AP-HP), 75475 Paris (Cedex 10), France
The metabolism of all-trans retinoic acid (ATRA) has been
reported to be partly responsible for the in vivo
resistance to ATRA seen in the treatment of human acute promyelocytic
leukemia (APL). However, ATRA metabolism appears to be involved in the
growth inhibition of several cancer cell lines in vitro.
The purpose of this study was to evaluate the in vitro
activity of the principal metabolites of ATRA
[4-hydroxy-retinoic acid (4-OH-RA), 18-hydroxy-retinoic acid
(18-OH-RA), 4-oxo-retinoic acid (4-oxo-RA), and
5,6-epoxy-retinoic acid (5,6-epoxy-RA)] in NB4, a human promyelocytic
leukemia cell line that exhibits the APL diagnostic t(15;17)
chromosomal translocation and expresses the PML-RAR
fusion
protein. We established that the four ATRA metabolites were indeed
formed by the NB4 cells in vitro. NB4 cell growth was
inhibited (69–78% at 120 h) and cell cycle progression in the
G1 phase (82–85% at 120 h) was blocked by ATRA and
all of the metabolites at 1 µM concentration. ATRA and
its metabolites could induce NB4 cells differentiation with similar
activity, as evaluated by cell morphology, by the nitroblue
tetrazolium reduction test (82–88% at 120 h) or by the
expression of the maturation specific cell surface marker CD11c. In
addition, nuclear body reorganization to macropunctated
structures, as well as the degradation of PML-RAR, was found to be
similar for ATRA and all of its metabolites. Comparison of the relative
potency of the retinoids using the nitroblue tetrazolium reduction test
showed effective concentrations required to differentiate 50% of cells
in 72 h as follows: ATRA, 15.8 ± 1.7
nM; 4-oxo-RA, 38.3 ± 1.3 nM;
18-OH-RA, 55.5 ± 1.8 nM; 4-OH-RA,
79.8 ± 1.8 nM; and 5,6-epoxy-RA,
99.5 ± 1.5 nM. The ATRA metabolites were
found to exert their differentiation effects via the RAR nuclear
receptors, because the RAR-specific antagonist BMS614 blocked
metabolite-induced CD11c expression in NB4 cells. These data
demonstrate that the principal ATRA Phase 1 metabolites can elicit
leukemia cell growth inhibition and differentiation in
vitro through the RAR signaling pathway, and they suggest
that these metabolites may play a role in ATRA antileukemic activity
in vivo.
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