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Istituto di scienza dell'alimentazione

Torna all'elenco Contributi in rivista anno 2013

Contributo in rivista

Tipo: Articolo in rivista

Titolo: ABT-737 resistance in B-cells isolated from chronic lymphocytic leukemia patients and leukemia cell lines is overcome by the pleiotropic kinase inhibitor quercetin through Mcl-1 down-regulation

Anno di pubblicazione: 2013

Formato: Elettronico Cartaceo

Autori: Russo, M. and Spagnuolo, C. and Volpe, S. and Tedesco, I. and Bilotto, S. and Russo, G.L.

Affiliazioni autori: Institute of Food Sciences, National Research Council, 83100 Avellino, Italy; Division of Onco-Hematology, S.G. Moscati Hospital, 83100 Avellino, Italy

Autori CNR:


Lingua: inglese

Abstract: Chronic lymphocytic leukemia (CLL) is the most frequent form of leukemia in adult population and despite numerous studies, it is considered an incurable disease. Since CLL is characterized by overexpression of pro-survival Bcl-2 family members, treatments with their antagonists, such as ABT-737, represent a promising new therapeutic strategy. ABT-737 is a BH3 mimetic agent which binds Bcl-2, Bcl-XL and Bcl-w with high affinity, while weakly interacts with Mcl-1 and Bfl-1. Previous studies demonstrated that quercetin, a flavonoid naturally present in food and beverages, was able to sensitize B-cells isolated from CLL patients to apoptosis when associated with death ligands or fludarabine, through a mechanism involving Mcl-1 down-regulation. Here, we report that the association between ABT-737 and quercetin synergistically induces apoptosis in B-cells and in five leukemic cell lines (Combination Index <1). Peripheral blood mononuclear cell from healthy donors were not affected by quercetin treatment. The molecular pathways triggered by quercetin have been investigated in HPB-ALL cells, characterized by the highest resistance to both ABT-737 and quercetin when applied as single molecules, but highly sensitivity to the co-treatment. In this cell line, quercetin down-regulated Mcl-1 through the inhibition of PI3K/Akt signaling pathway, leading to Mcl-1 instability. The same mechanism was confirmed in B-cells. These results may open new clinical perspectives based on a translational approach in CLL therapy. © 2013 Elsevier Inc.

Lingua abstract: inglese

Pagine da: 927

Pagine a: 936

Pagine totali: 9


Biochemical pharmacology Pergamon Press,
Paese di pubblicazione: Regno Unito
Lingua: inglese
ISSN: 0006-2952

Numero volume: 85

Numero fascicolo: 7

DOI: 10.1016/j.bcp.2013.01.011

Referee: Sì: Internazionale

Indicizzato da: Scopus [2-s2.0-84874657510]

Parole chiave:

  • 4 [4 (4' chloro 2 biphenylylmethyl) 1 piperazinyl] n [4 [3 dimethylamino 1 (phenylthiomethyl)propylamino] 3 nitrobenzenesulfonyl]benzamide
  • phosphatidylinositol 3 kinase
  • protein kinase B
  • protein mcl 1
  • quercetin
  • apoptosis
  • article
  • B lymphocyte
  • cancer resistance
  • cell isolation
  • chronic lymphatic leukemia
  • controlled study
  • dose response
  • down regulation
  • drug potentiation
  • drug sensitivity
  • human
  • human cell
  • leukemia cell
  • peripheral blood mononuclear cell
  • priority journal
  • Antineoplastic Agents
  • Apoptosis
  • B-Lymphocytes
  • Biphenyl Compounds
  • Cell Line
  • Tumor
  • Drug Resistance
  • Neoplasm
  • Drug Synergism
  • Humans
  • Leukemia
  • Leukemia
  • Lymphocytic
  • Chronic
  • B-Cell
  • Mitogen-Activated Protein Kinase Kinases
  • Nitrophenols
  • Phosphatidylinositol 3-Kinases
  • Piperazines
  • Protein Stability
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2
  • Quercetin
  • Signal Transduction
  • Sulfonamides

URL: http://www.scopus.com/inward/record.url?eid=2-s2.0-84874657510&partnerID=40&md5=778e845019a6b6c6a77682b307e61d24

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