@article{10902/32207,
year = {2011},
url = {https://hdl.handle.net/10902/32207},
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.},
organization = {Funding: this work was supported by a grant from the Ministry of Science and Innovation of Spain (BFU2006-01813/BMC and RD06/0020/ 0041).The CIC receives support from the European Community through the regional development funding program (FEDER).This work was also supported by the ‘AcciónTransversal del Cáncer’ project, through an agreement between the Instituto de Salud Carlos III (ISCIII), the Spanish Ministry of Science and Innovation, and the Cancer Research Foundation of Salamanca University. Our group also receives support from the Junta de Castilla y Léon through ‘Ayudas destinadas a financiar programas de actividad investigadora a realizar por grupos de investigación de excelencia de Castilla y León’.},
publisher = {Ferrata Storti Foundation},
publisher = {Haematologica, 2011, 117(13), 3613-3616},
title = {Zalypsis has in vitro activity in acute myeloid blasts and leukemic progenitor cells through the induction of a DNA damage response.},
author = {Paiva, Bruno and Vídriales, María-Belén and Pérez, José J. and López-Berges, María-Consuelo and García-Sanz, Ramón and Ocio San Miguel, Enrique María and Ocio San Miguel, Enrique María and De Las Heras, Natalia and Cuello, Rebeca and De Coca, Alfonso García and Pardal, Emilia and Alonso, José and Sierra, Magdalena and Bárez, Abelardo and Hernández, José and Suárez, Lissbett and Galende, Josefina and Mateos, María-Victoria and San Miguel, Jesús F.},
}