Publicaciones científicas

A novel FTY720 analogue targets SET-PP2A interaction and inhibits growth of acute myeloid leukemia cells without inducing cardiac toxicity

01-ene-2020 | Revista: Cancer Letters

Carmen Vicente, Elena Arriazu, Elena Martínez-Balsalobre, Irene Peris, Nerea Marcotegui, Patricia García-Ramírez, Raffaella Pippa, Obdulia Rabal, Julen Oyarzábal, Elizabeth Guruceaga, Felipe Prósper, María C Mateos, María L Cayuela, María D Odero


Acute myeloid leukemia (AML) is an aggressive disease associated with very poor prognosis. Most patients are older than 60 years, and in this group only 5-15% of cases survive over 5 years. Therefore, it is urgent to develop more effective targeted therapies. Inactivation of protein phosphatase 2 A (PP2A) is a recurrent event in AML, and overexpression of its endogenous inhibitor SET is detected in ~30% of patients. The PP2A activating drug FTY720 has potent anti-leukemic effects; nevertheless, FTY720 induces cardiotoxicity at the anti-neoplastic dose. Here, we have developed a series of non-phosphorylable FTY720 analogues as a new therapeutic strategy for AML.

Our results show that the lead compound CM-1231 re-activates PP2A by targeting SET-PP2A interaction, inhibiting cell proliferation and promoting apoptosis in AML cell lines and primary patient samples. Notably, CM-1231 did not induce cardiac toxicity, unlike FTY720, in zebrafish models, and reduced the invasion and aggressiveness of AML cells more than FTY720 in zebrafish xenograft models. In conclusion, CM-1231 is safer and more effective than FTY720; therefore, this compound could represent a novel and promising approach for treating AML patients with SET overexpression.

CITA DEL ARTÍCULO  Cancer Lett. 2020 Jan 1;468:1-13. doi: 10.1016/j.canlet.2019.10.007. 

Nuestros autores

Investigadora adscrita al proyecto del Grupo de Patología Mieloide del Cima Universidad de Navarra
Carmen Vicente Vázquez
Nerea Marcotegui Arza
Elizabet Guruceaga Martínez
Técnico de Investigación Bioinformático Plataforma Bioinformática