1. Sodium dichloroacetate exhibits anti-leukemic activity in B-chronic lymphocytic leukemia (B-CLL) and synergizes with the p53 activator Nutlin-3
- Author
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Laura Brunelli, Gian Matteo Rigolin, Paola Secchiero, Giorgio Zauli, Elisabetta Melloni, Fabio Casciano, Claudio Celeghini, Antonio Cuneo, Erika Rimondi, Chiara Agnoletto, C., Agnoletto, E., Melloni1, F., Casciano, G. M., Rigolin, Rimondi, Erika, Celeghini, Claudio, L., Brunelli, A., Cuneo, P., Secchiero, and G., Zauli
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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 - 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.
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- 2014