The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway
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Chiara Agnoletto1, Laura Brunelli1, Elisabetta Melloni1, Roberta Pastorelli2, Fabio Casciano1, Erika Rimondi3, Gian Matteo Rigolin4, Antonio Cuneo4, Paola Secchiero1 and Giorgio Zauli5
1 Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
2 Institute of Pharmacological Researches, IRCCS “Mario Negri”, Milano, Italy
3 Department of Life Science, University of Trieste, Trieste, Italy
4 Department of Medical Sciences, University of Ferrara-Arcispedale S. Anna, Ferrara, Italy
5 Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste, Italy
Paola Secchiero, email:
Keywords: Sodium dichloroacetate, B-CLL, p21, proteomics, cytotoxicity
Received: October 27, 2014 Accepted: December 09, 2014 Published: December 10, 2014
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.
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