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Titolo:
A SUSTAINED INCREASE IN THE ENDOGENOUS LEVEL OF CAMP REDUCES THE RETINOID CONCENTRATION REQUIRED FOR APL CELL MATURATION TO NEAR PHYSIOLOGICAL LEVELS
Autore:
QUENECHDU N; RUCHAUD S; KHELEF N; GUISO N; LANOTTE M;
Indirizzi:
UNIV PARIS,HOP ST LOUIS,INSERM U496,INST HEMATOL F-75475 PARIS 10 FRANCE UNIV PARIS,HOP ST LOUIS,INSERM U496,INST HEMATOL F-75475 PARIS 10 FRANCE INST PASTEUR,LAB BORDETELLA PARIS FRANCE
Titolo Testata:
Leukemia
fascicolo: 11, volume: 12, anno: 1998,
pagine: 1829 - 1833
SICI:
0887-6924(1998)12:11<1829:ASIITE>2.0.ZU;2-A
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACUTE PROMYELOCYTIC LEUKEMIA; ADENYLATE CYCLASE-HEMOLYSIN; PML-RAR-ALPHA; BORDETELLA-PERTUSSIS; NB4 CELLS; PROTEIN-KINASE; ACID; DIFFERENTIATION; TRANSLOCATION; APOPTOSIS;
Keywords:
RETINOIDS; CAMP; LEUKEMIA; DIFFERENTIATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
37
Recensione:
Indirizzi per estratti:
Citazione:
N. Quenechdu et al., "A SUSTAINED INCREASE IN THE ENDOGENOUS LEVEL OF CAMP REDUCES THE RETINOID CONCENTRATION REQUIRED FOR APL CELL MATURATION TO NEAR PHYSIOLOGICAL LEVELS", Leukemia, 12(11), 1998, pp. 1829-1833

Abstract

cAMP-dependent signal transduction co-operates with retinoids to induce acute promyelocytic leukaemia (APL) cell maturation. The rationale of this work was to determine whether signal cross-talk could be used to decrease the pharmacological doses of retinoids in the treatment ofAPL. When only the basal level of adenylate-cyclase (AC) activity is present in NB4 cells, up to 1 mu M concentration of all-trans retinoicacid (RA) is required for full maturation (100%). In these conditions, with only 10 nM RA less than 20% of cells will differentiate. Although the use of membrane receptor agonists to activate AC has been proved to synergize with RA treatment, these agents were never as potent ascell permeant cAMP analogues. Analogues have disadvantages since cleavage by serum and cellular phosphodiesterases generates metabolites which interfere in cellular response. In the present study, we observed cell maturation by engrafting an autonomous Bordetella pertussis AC which steadily delivers natural cAMP into the cell. The enzyme alone hadno effect on cell maturation. Importantly, cell maturation was increased in a dose-dependent manner when the bacterial AC (1 ng/ml to 1 mu g/ml) was used to potentiate the effects of low doses RA (10 nM). Morethan 50% of cells matured with only 10 nM of RA and 200 ng/ml of B. pertussis AC. The maturation response was significantly increased when lower amounts of enzyme were repetitively added to the culture to compensate for enzymatic decay. These results indicate that a sustained ACactivity enhanced cell maturation. We were able to reduce to 3 nM theRA requirement, provided that a minimal amount (20 ng/ml) of B. pertussis AC was added every 12 h in culture. Membrane signalling maintaining high the level of cAMP substantially improved the efficacy of APL cell maturation by retinoids. Therefore, therapeutic benefits are expected by lowering the concentration of RA towards physiological (nanomolar) levels, thus reducing the side-effects of the drug. cAMP-elevatingdrugs that act on a post-cyclase target (cyclic-nucleotide phosphodiesterases) or cell-targeted drug carriers (cAMP and RA loaded liposomes) should be evaluated as maturation therapies combining the activationof multiple signalling pathways.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/11/20 alle ore 00:04:06