Buscar

Estamos realizando la búsqueda. Por favor, espere...

Zalypsis has in vitro activity in acute myeloid blasts and leukemic progenitor cells through the induction of a DNA damage response.

Abstract: Background: Although the majority of patients with acute myeloid leukemia initially respond to conventional chemotherapy, relapse is still the leading cause of death, probably because of the presence of leukemic stem cells that are insensitive to current therapies. We investigated the antileukemic activity and mechanism of action of zalypsis, a novel alkaloid of marine origin. Design and methods: The activity of zalypsis was studied in four acute myeloid leukemia cell lines and in freshly isolated blasts taken from patients with acute myeloid leukemia before they started therapy. Zalypsis-induced apoptosis of both malignant and normal cells was measured using flow cytometry techniques. Gene expression profiling and western blot studies were performed to assess the mechanism of action of the alkaloid. Results: Zalypsis showed a very potent antileukemic activity in all the cell lines tested and potentiated the effect of conventional antileukemic drugs such as cytarabine, fludarabine and daunorubicin. Interestingly, zalypsis showed remarkable ex vivo potency, including activity against the most immature blast cells (CD34(+) CD38(-) Lin(-)) which include leukemic stem cells. Zalypsis-induced apoptosis was the result of an important deregulation of genes involved in the recognition of double-strand DNA breaks, such as Fanconi anemia genes and BRCA1, but also genes implicated in the repair of double-strand DNA breaks, such as RAD51 and RAD54. These gene findings were confirmed by an increase in several proteins involved in the pathway (pCHK1, pCHK2 and pH2AX). Conclusions: The potent and selective antileukemic effect of zalypsis on DNA damage response mechanisms observed in acute myeloid leukemia cell lines and in patients' samples provides the rationale for the investigation of this compound in clinical trials.

 Fuente: Haematologica, 2011, 117(13), 3613-3616

 Editorial: Ferrata Storti Foundation

 Año de publicación: 2011

 Nº de páginas: 9

 Tipo de publicación: Artículo de Revista

 DOI: 10.3324/haematol.2010.036400

 ISSN: 0390-6078,1592-8721

 Url de la publicación: https://doi.org/10.3324/haematol.2010.036400

Autoría

PAIVA, BRUNO

VÍDRIALES, MARÍA-BELÉN

PÉREZ, JOSÉ J.

LÓPEZ-BERGES, MARÍA-CONSUELO

GARCÍA-SANZ, RAMÓN

OCIO, ENRIQUE M.

DE LAS HERAS, NATALIA

CUELLO, REBECA

DE COCA, ALFONSO GARCÍA

PARDAL, EMILIA

ALONSO, JOSÉ

SIERRA, MAGDALENA

BÁREZ, ABELARDO

HERNÁNDEZ, JOSÉ

SUÁREZ, LISSBETT

GALENDE, JOSEFINA

MATEOS, MARÍA-VICTORIA

SAN MIGUEL, JESÚS F.