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Titolo:
Granulocytic differentiation of human NB4 promyelocytic leukemia cells induced by all-trans retinoic acid metabolites
Autore:
Idres, N; Benoit, G; Flexor, MA; Lanotte, M; Chabot, GG;
Indirizzi:
Univ Paris 07, Hop St Louis, Inst Univ Hematol, Ctr Hayem,INSERM,U496,AP HP, F-75475 Paris 10, France Univ Paris 07 Paris France 10 NSERM,U496,AP HP, F-75475 Paris 10, France
Titolo Testata:
CANCER RESEARCH
fascicolo: 2, volume: 61, anno: 2001,
pagine: 700 - 705
SICI:
0008-5472(20010115)61:2<700:GDOHNP>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
PML-RAR-ALPHA; BREAST-CANCER CELLS; CLINICAL-PHARMACOLOGY; BIOLOGICAL-ACTIVITY; BINDING PROTEIN; X-RECEPTOR; T(15-17); TRANSLOCATION; RESISTANCE; PROLIFERATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
53
Recensione:
Indirizzi per estratti:
Indirizzo: Chabot, GG Univ Paris 07, Hop St Louis, Inst Univ Hematol, Ctr Hayem,INSERM,U496,AP HP, 1 Ave Claude Vellefaux, F-75475 Paris 10, France Univ Paris 07 1 Ave Claude Vellefaux Paris France 10 0, France
Citazione:
N. Idres et al., "Granulocytic differentiation of human NB4 promyelocytic leukemia cells induced by all-trans retinoic acid metabolites", CANCER RES, 61(2), 2001, pp. 700-705

Abstract

The metabolism of all-trans retinoic acid (ATRA) has been reported to be partly responsible for the ill vivo resistance to ATRA seen in the treatmentof human acute promyelocytic leukemia (APL). However, ATRA metabolism appears to be involved in the growth inhibition of several cancer cell lines invitro. The purpose of this study was to evaluate the ill vitro activity ofthe 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 translocationand expresses the PML-RAR alpha 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 G(1) phase (82-85% at 120 h) was blocked by ATRA and all of the metabolites at 1 muM 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 expressionof the maturation specific cell surface marker CD11c. In addition, nuclearbody reorganization to macropunctated structures, as well as the degradation of PML-RAR alpha, 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 nhl; 4-OH-RA, 79.8 +/- 1.8 nar; and 5,6-epoxy-RA, 99.5 +/- 1.5 nhl, The ATRA metabolites were found to exert their differentiation effects via the RAR alpha nuclear receptors, because the RAR alpha -specific antagonist BMS614 blocked metabolite-induced CD11c expression in NB4 cells. These data demonstrate that the principal ATRAPhase 1 metabolites can elicit leukemia cell growth inhibition and differentiation in vitro through the RAR alpha signaling pathway, and they suggestthat these metabolites may play a role in ATRA antileukemic activity in vivo.

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Documento generato il 27/11/20 alle ore 22:18:15