title: Sodium dichloroacetate exhibits anti-leukemic activity in B-chronic lymphocytic leukemia (B-CLL) and synergizes with the p53 activator Nutlin-3.
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.
authors: Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy. These two authors equally contributed to this work.
authors: Chiara
authors: C
authors: Agnoletto
authors: Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy. These two authors equally contributed to this work.
authors: Elisabetta
authors: E
authors: Melloni
authors: Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors: Fabio
authors: F
authors: Casciano
authors: Department of Medical Sciences, University of Ferrara-Arcispedale S. Anna, Ferrara, Italy.
authors: Gian Matteo
authors: GM
authors: Rigolin
authors: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors: Erika
authors: E
authors: Rimondi
authors: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors: Claudio
authors: C
authors: Celeghini
authors: Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors: Laura
authors: L
authors: Brunelli
authors: Department of Medical Sciences, University of Ferrara-Arcispedale S. Anna, Ferrara, Italy.
authors: Antonio
authors: A
authors: Cuneo
authors: Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors: Paola
authors: P
authors: Secchiero
authors: Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy.
authors: Giorgio
authors: G
authors: Zauli
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D003999:Dichloroacetic Acid / Q000378:metabolism*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007093:Imidazoles; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D003999:Dichloroacetic Acid