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Sodium dichloroacetate exhibits anti-leukemic activity in B-chronic lymphocytic leukemia (B-CLL) and synergizes with the p53 activator Nutlin-3
- Source :
- Scopus-Elsevier, ResearcherID, Oncotarget
- Publication Year :
- 2014
-
Abstract
- // Chiara Agnoletto 1,* , Elisabetta Melloni 1,* , Fabio Casciano 1 , Gian Matteo Rigolin 2 , Erika Rimondi 3 , Claudio Celeghini 3 , Laura Brunelli 1 , Antonio Cuneo 2 , Paola Secchiero 1 , Giorgio Zauli 4 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 p53 wild-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.
- Subjects :
- Male
Sodium dichloroacetate, B-CLL, Nutlin-3
Sodium dichloroacetate
Piperazines
NO
chemistry.chemical_compound
Puma
Humans
Medicine
Cytotoxic T cell
Cytotoxicity
Aged
Aged, 80 and over
Dichloroacetic Acid
biology
p21
business.industry
Imidazoles
Nutlin-3
Drug Synergism
Sodium Dichloroacetate
Transfection
Nutlin
B-CLL
Middle Aged
biology.organism_classification
medicine.disease
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia
Oncology
chemistry
Cell culture
Cancer research
Female
Tumor Suppressor Protein p53
business
Research Paper
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Scopus-Elsevier, ResearcherID, Oncotarget
- Accession number :
- edsair.doi.dedup.....e4d1297ecedd68358bdec566e7f385c8