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: Chiara Agnoletto, Laura Brunelli, Elisabetta Melloni, Roberta Pastorelli, Fabio Casciano, Erika Rimondi, Gian Matteo Rigolin, Antonio Cuneo, Paola Secchiero, Giorgio Zauli
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 4 Pg. 2385-96 (Feb 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25544776 (Publication Type: Journal Article)

Chemical References

• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Nuclear Factor 90 Proteins
• Tumor Suppressor Protein p53
• Dichloroacetic Acid

Topics

• Aged
• Blotting, Western
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• Cells, Cultured
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Dichloroacetic Acid (pharmacology)
• Female
• Gene Expression Regulation, Leukemic (drug effects)
• HL-60 Cells
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, genetics, metabolism)
• Male
• Middle Aged
• Models, Genetic
• Mutation
• Nuclear Factor 90 Proteins (genetics, metabolism)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Suppressor Protein p53 (genetics)