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Oncotarget. 2014 Jun 30;5(12):4347-60.

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

Author information

1
Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy. These two authors equally contributed to this work.
2
Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
3
Department of Medical Sciences, University of Ferrara-Arcispedale S. Anna, Ferrara, Italy.
4
Department of Life Sciences, University of Trieste, Trieste, Italy.
5
Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy.

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.

PMID:
24962518
PMCID:
PMC4147328
DOI:
10.18632/oncotarget.2018
[Indexed for MEDLINE]
Free PMC Article

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