RESUMEN
Adult Acute Lymphoblastic Leukemia (ALL) therapies have been improved by pediatric-like approaches. However, treatment failures and relapses are common and new markers are needed to identify patients with poor prognosis in prospective trials. The p16(INK4A)/CDK4-6/pRb pathway and telomerase activity, which are implicated in cell activation and aging, were analyzed to identify new prognostic markers. Proteins of the p16(INK4A)/CDK4-6/pRb pathway and telomerase activity were analyzed in 123 adult B-cell precursor (BCP) ALL cases included in the GRAALL/GRAAPH trials. We found a significantly increased expression of p16(INK4A) in BCP-ALLs with MLL rearrangement. Telomerase activity was significantly lower in Philadelphia chromosome-negative/IKAROS-deleted (BCR-ABL1(-)/IKAROS(del)) cases compared to Philadelphia chromosome-positive (BCR-ABL1+) BCP-ALLs. In BCR-ABL1+ ALLs, high CDK4 expression, phosphorylated pRb (p-pRb) and telomerase activity were significantly associated with a shorter disease-free survival (DFS) and event-free survival (EFS). Enhanced p16(INK4A) expression was only related to a significantly shorter DFS. In vitro analyses of normal stimulated lymphocytes after short- and long-term cultures demonstrated that the observed protein variations of poor prognosis in BCR-ABL1+ ALLs may be related to cell activation but not to cell aging. For these patients, our findings argue for the development of therapeutic strategies including the addition of new lymphocyte activation inhibitors to current treatments.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteína de Retinoblastoma/metabolismo , Telomerasa/metabolismo , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Western Blotting , Estudios de Casos y Controles , Células Cultivadas , Análisis Citogenético , Femenino , Estudios de Seguimiento , Humanos , Inmunofenotipificación , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Fosforilación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Adulto JovenRESUMEN
Grapefruit juice is responsible for many drug interactions but the exact components involved in this interaction are not precisely known. Flavonoids and furocoumarin derivatives such as naringenin and bergamottin, respectively, could be involved in the inhibition of drug metabolism. The objective of this paper is to investigate in vitro the possible metabolic hepatic interaction between simvastatin (SV) and bergamottin (BG) and thus to compare its effects to those of naringenin (NRG) the aglycone form of naringin (NR) (a flavonoid present in grapefruit juice). In human and rat microsomes and in rat hepatocytes, BG was found to be a mixed type inhibitor of SV metabolism. In rat liver microsomes the K(i) value of BG (K(i)=174+/-36 microM) is higher than the K(i) value of NRG (K(i)=29+/-11 microM). However, in human liver microsomes the K(i) values are similar in BG and NRG (K(i)=34+/-5 microM and 29+/-11 microM, respectively). Moreover, it seems that there is an interspecies difference between human and rat hepatic metabolism of SV involving different isoenzymes of CYP 450. In conclusion, our study shows that BG inhibits SV metabolism. BG and NRG could therefore be applied as markers in food-drug interaction studies in order to adjust posology.