title: The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway.
abstract: B-chronic lymphocytic leukemia (B-CLL) patients harboring p53 mutations are invariably refractory to therapies based on purine analogues and have limited treatment options and poor survival. Having recently demonstrated that the mitochondria-targeting small molecule sodium dichloroacetate (DCA) exhibits anti-leukemic activity in p53wild-type B-CLL cells, the aim of this study was to evaluate the effect of DCA in p53mutated B-CLL cells and in p53mutated/null leukemic cell lines. DCA exhibited comparable cytotoxicity in p53wild-type and p53mutated B-CLL patient cell cultures, as well as in p53mutated B leukemic cell lines (MAVER, MEC-1, MEC-2). At the molecular level, DCA promoted the transcriptional induction of p21 in all leukemic cell types investigated, including p53null HL-60. By using a proteomic approach, we demonstrated that DCA up-regulated the ILF3 transcription factor, which is a known regulator of p21 expression. The role of the ILF3/p21 axis in mediating the DCA anti-leukemic activity was underscored by knocking-down experiments. Indeed, transfection with ILF3 and p21 siRNAs significantly decreased both the DCA-induced p21 expression and the DCA-mediated cytotoxicity. Taken together, our results emphasize that DCA is a small molecule that merits further evaluation as a therapeutic agent also for p53mutated leukemic cells, by acting through the induction of a p53-independent pathway.
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Agnoletto
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Brunelli
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Melloni
authors.affiliation: Institute of Pharmacological Researches, IRCCS "Mario Negri", Milano, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Pastorelli
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Casciano
authors.affiliation: Department of Life Science, University of Trieste, Trieste, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Rimondi
authors.affiliation: Department of Medical Sciences, University of Ferrara-Arcispedale S. Anna, Ferrara, Italy.
authors.forename: Gian Matteo
authors.initials: GM
authors.lastname: Rigolin
authors.affiliation: Department of Medical Sciences, University of Ferrara-Arcispedale S. Anna, Ferrara, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuneo
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
authors.affiliation: Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
mesh_terms: D000368:Aged; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D050779:Nuclear Factor 90 Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050779:Nuclear Factor 90 Proteins; D016159:Tumor Suppressor Protein p53; D003999:Dichloroacetic Acid