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.
Highlights
Most cancers possess a near-universal metabolic phenotype known as the ‘Warburg effect’, which is characterized by enhanced glycolytic flux for ATP production, glucose to lactate conversion and reduced mitochondrial oxidative phosphorylation, even under aerobic conditions [1,2,3]
peripheral blood mononuclear cells (PBMC) obtained from healthy donors were significantly less susceptible to DCA cytotoxicity as compared to primary B-chronic lymphocytic leukemia (B-CLL) cells, with IC50 mean values (±SD) of cytotoxicity of 198±106 mM and 93±52 mM at 24 and 48 hours of treatment (Figure 1A-B), clearly showing that normal PBMC were completely resistant to DCA effects at concentrations ≤10 mM
In line with previous data obtained in solid tumor cell models [4,5,6,7,8,9,10,11,12,13,14] and multiple myeloma [15], we have demonstrated for the first time that DCA promoted a significant cytotoxicity in primary B-CLL samples but not in normal PBMC
Summary
Most cancers possess a near-universal metabolic phenotype known as the ‘Warburg effect’, which is characterized by enhanced glycolytic flux for ATP production, glucose to lactate conversion and reduced mitochondrial oxidative phosphorylation, even under aerobic conditions [1,2,3]. There is growing evidence that the mitochondria might be primary targets in cancer therapeutics instead of simple bystanders during cancer development. This cancer-specific metabolic remodeling can be reversed by dichloroacetate (DCA), a mitochondria-targeting small molecule able to penetrate most tissues after oral administration [4]. DCA shows several interesting characteristics, such as effectiveness in a variety of solid tumor cell lines and relatively low toxicity on normal cells. Most of the current studies on DCA have been performed on solid tumors, such as non-small cell lung cancer, breast cancer and most glioblastoma cell lines [4,5]. Since leukemic cell lines use glycolysis and non-glucose bioenergetic pathways such as fatty www.impactjournals.com/oncotarget
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