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.
Highlights
Emerging data indicate that cancer associated oxidative stress, resulting from the accumulation of reactive oxygen species and leading to genetic instability and drug resistance [1,2], might be involved in the pathogenesis of B-chronic lymphocytic leukemia (B-CLL) [3]
Since B-CLL patients characterized by p53 dysfunction have limited treatment options and poor overall survival [16,18,19], in the first set of experiments we comparatively evaluated the in vitro effect of DCA assessed on B-CLL patient cells characterized by either p53 wild-type or harboring TP53 mutations (Table 1)
We have recently demonstrated that the mitochondria-targeting small molecule DCA promoted cytotoxicity in p53wild-type primary B-CLL cells and B leukemic cell lines at concentrations which marginally affected primary normal peripheral blood mononuclear cells [15]
Summary
Emerging data indicate that cancer associated oxidative stress, resulting from the accumulation of reactive oxygen species and leading to genetic instability and drug resistance [1,2], might be involved in the pathogenesis of B-chronic lymphocytic leukemia (B-CLL) [3]. The mitochondria might be primary targets of cancer therapeutics instead of simple bystanders during cancer development. In this context, there is an increasing interest for the therapeutic potentiality of the mitochondria-targeting dichloroacetate (DCA) against malignant cells. We have demonstrated that DCA is cytotoxic in p53wild-type primary B-CLL patient cells and in p53wild-type B leukemic cell lines [15], when used in the same range of concentrations previously employed in in vitro studies performed in solid tumors and multiple myeloma cells [10,11,12,14]. We found that in www.impactjournals.com/oncotarget p53wild-type B leukemic cells DCA activates p53 and potently synergizes with Nutlin-3, a non-genotoxic activator of the p53 pathway [15]
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