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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
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PAIVA, BRUNO
VÍDRIALES, MARÍA-BELÉN
PÉREZ, JOSÉ J.
LÓPEZ-BERGES, MARÍA-CONSUELO
GARCÍA-SANZ, RAMÓN
ENRIQUE MARIA OCIO SAN MIGUEL
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.
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