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

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...

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Bibliographic Details
Published in:Oncotarget 2014-06, Vol.5 (12), p.4347-4360
Main Authors: Agnoletto, Chiara, Melloni, Elisabetta, Casciano, Fabio, Rigolin, Gian Matteo, Rimondi, Erika, Celeghini, Claudio, Brunelli, Laura, Cuneo, Antonio, Secchiero, Paola, Zauli, Giorgio
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
Dichloroacetic Acid - metabolism
Drug Synergism
Female
Humans
Imidazoles
Leukemia, Lymphocytic, Chronic, B-Cell - genetics
Male
Middle Aged
Piperazines
Research Paper
Tumor Suppressor Protein p53 - metabolism
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.2018