Oncotarget

Research Papers:

Sodium dichloroacetate exhibits anti-leukemic activity in B-chronic lymphocytic leukemia (B-CLL) and synergizes with the p53 activator Nutlin-3

Chiara Agnoletto, Elisabetta Melloni, Fabio Casciano, Gian Matteo Rigolin, Erika Rimondi, Claudio Celeghini, Laura Brunelli, Antonio Cuneo, Paola Secchiero _ and Giorgio Zauli

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Oncotarget. 2014; 5:4347-4360. https://doi.org/10.18632/oncotarget.2018

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Abstract

Chiara Agnoletto1,*, Elisabetta Melloni1,*, Fabio Casciano1, Gian Matteo Rigolin2, Erika Rimondi3, Claudio Celeghini3, Laura Brunelli1, Antonio Cuneo2, Paola Secchiero1, Giorgio Zauli4

1 Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy

2 Department of Medical Sciences, University of Ferrara-Arcispedale S.Anna, Ferrara, Italy

3 Department of Life Sciences, University of Trieste, Trieste, Italy

4 Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste, Italy

* These two authors equally contributed to this work

Correspondence:

Paola Secchiero, email:

Keywords: Sodium dichloroacetate, Nutlin-3, B-CLL, p21

Received: March 21, 2014 Accepted: May 26, 2014 Published: May 26, 2014

Abstract

The anti-leukemic activity of the mitochondria-targeting small molecule sodium dichloroacetate (DCA), used alone and in association with the small molecule inhibitor of the p53/MDM2 interaction Nutlin-3, was analyzed in primary B-chronic lymphocytic leukemia (B-CLL) samples (n=22), normal peripheral blood cells (n=10) and in p53wild-type EHEB, JVM-2, JVM-3 B lymphoblastoid cell lines. DCA exhibited a dose-dependent anti-leukemic activity in both primary B-CLL and B leukemic cell lines with a functional p53 status and showed a synergistic cytotoxic activity when used in combination with Nutlin-3. At the molecular level, DCA positively regulated p53 activity, as documented by post-transcriptional modifications of p53 protein, and synergized with Nutlin-3 in increasing the expression of the p53-target genes MDM2, PUMA, TIGAR and in particular p21. The potential role of p21 in mediating the DCA+Nutlin-3 anti-leukemic activity was underscored in knocking-down experiments. Indeed, transfection of leukemic cells with p21 siRNAs significantly decreased the DCA+Nutlin-3-induced cytotoxicity. Taken together, our data emphasize that DCA is a molecule that merits to be further evaluated as a chemotherapeutic agent for B-CLL, likely in combination with other therapeutic compounds.


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