Sodium dichloroacetate exhibits anti-leukemic activity in B-chronic lymphocytic leukemia (B-CLL) and synergizes with the p53 activator Nutlin-3

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.

• Publication year

  2014

• Venue

  OncoTarget

• Publication date

  2014-05-26

• Fields of study

  Medicine

• Identifiers
  DOI 10.18632/ONCOTARGET.2018PMID 24962518PMCID 4147328
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• M(o)TOR of pseudo-hypoxic state in aging: Rapamycin to the rescue

  2014cited by this paper
• Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

  2013cited by this paper
• Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib

  2013influential reference
• An evaluation of small-molecule p53 activators as chemoprotectants ameliorating adverse effects of anticancer drugs in normal cells

  2012cited by this paper
• New Horizons in Cancer Therapy: Manipulating Tumour Metabolism.

  2012cited by this paper
• The sorafenib plus nutlin-3 combination promotes synergistic cytotoxicity in acute myeloid leukemic cells irrespectively of FLT3 and p53 status

  2012cited by this paper
• Functional Analysis of the ATM-p53-p21 Pathway in the LRF CLL4 Trial: Blockade at the Level of p21 Is Associated with Short Response Duration

  2012influential reference
• Cyclotherapy: opening a therapeutic window in cancer treatment

  2012cited by this paper
• Cotreatment with dichloroacetate and omeprazole exhibits a synergistic antiproliferative effect on malignant tumors.

  2012influential reference
• The Interfaces Between Signal Transduction Pathways: IGF-1/mTor, p53 and the Parkinson Disease Pathway

  2012cited by this paper
• Combination of Sulindac and Dichloroacetate Kills Cancer Cells via Oxidative Damage

  2012influential reference
• Cyclotherapy: opening a therapeutic window in cancer treatment.

  2012cited by this paper
• Novel molecular mechanisms of antitumor action of dichloroacetate against T cell lymphoma: Implication of altered glucose metabolism, pH homeostasis and cell survival regulation.

  2012cited by this paper
• Synergistic Antitumor Effect of Dichloroacetate in Combination with 5-Fluorouracil in Colorectal Cancer

  2011influential reference
• Targeting metabolism with arsenic trioxide and dichloroacetate in breast cancer cells

  2011influential reference
• Exploring long-term protection of normal human fibroblasts and epithelial cells from chemotherapy in cell culture

  2011cited by this paper
• Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate

  2011cited by this paper
• Recent advances in the therapeutic perspectives of Nutlin-3.

  2011cited by this paper
• Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxide, driving the Warburg effect

  2011cited by this paper
• The power of chemotherapeutic engineering: Arresting cell cycle and suppressing senescence to protect from mitotic inhibitors

  2011cited by this paper
• miR-34a Induces the Downregulation of Both E2F1 and B-Myb Oncogenes in Leukemic Cells

  2011cited by this paper
• Sodium dichloroacetate selectively targets cells with defects in the mitochondrial ETC

  2010cited by this paper
• Evaluation of an Actinomycin D/VX-680 aurora kinase inhibitor combination in p53-based cyclotherapy

  2010cited by this paper
• Dasatinib Plus Nutlin-3 Shows Synergistic Antileukemic Activity in Both p53wild-type and p53mutated B Chronic Lymphocytic Leukemias by Inhibiting the Akt Pathway

  2010cited by this paper
• Paradoxical suppression of cellular senescence by p53

  2010cited by this paper
• Energy metabolism of leukemia cells: glycolysis versus oxidative phosphorylation

  2010cited by this paper
• Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo

  2010influential reference
• Metabolic Modulation of Glioblastoma with Dichloroacetate

  2010influential reference
• Selection of cancer cells with repressed mitochondria triggers colon cancer progression.

  2010cited by this paper
• Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells.

  2009cited by this paper
• Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism.

  2009cited by this paper
• Oxygen Consumption Can Regulate the Growth of Tumors, a New Perspective on the Warburg Effect

  2009cited by this paper
• Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer

  2008cited by this paper
• Tumor necrosis factor-related apoptosis-inducing ligand and the regulation of hematopoiesis

  2008cited by this paper
• Dichloroacetate induces apoptosis in endometrial cancer cells.

  2008cited by this paper
• Dichloroacetate (DCA) sensitizes both wild‐type and over expressing Bcl‐2 prostate cancer cells in vitro to radiation

  2008cited by this paper
• The MDM2 inhibitor Nutlins as an innovative therapeutic tool for the treatment of haematological malignancies.

  2008cited by this paper
• A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth.

  2007influential reference
• Dichloroacetate Induces Apoptosis in Endometrial Cancer Cells

  2007influential reference
• Cancer's molecular sweet tooth and the Warburg effect.

  2006cited by this paper
• Extracellular HIV-1 Tat protein induces the rapid Ser133 phosphorylation and activation of CREB transcription factor in both Jurkat lymphoblastoid T cells and primary peripheral blood mononuclear cells.

  1998cited by this paper
• Role of the extracellular domain of human herpesvirus 7 glycoprotein B in virus binding to cell surface heparan sulfate proteoglycans

  1997cited by this paper
• IMP dehydrogenase inhibitor, tiazofurin, induces apoptosis in K562 human erythroleukemia cells.

  1997cited by this paper
• An autocrine loop of HIV type-1 Tat protein responsible for the improved survival/proliferation capacity of permanently Tat-transfected cells and required for optimal HIV-1 LTR transactivating activity.

  1995cited by this paper
• Uninfected haematopoietic progenitor (CD34+) cells purified from the bone marrow of AIDS patients are committed to apoptotic cell death in culture

  1993cited by this paper
• Mitochondrial membrane potential in living cells.

  1988cited by this paper
• The establishment of cell lines from chronic B cell leukaemias: evidence of leukaemic origin by karyotypic abnormalities and Ig gene rearrangement.

  1988influential reference
• Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.

  1984cited by this paper

• The evolution of Nutlins as p53-MDM2 inhibitors

  2025cites this paper
• Multi-Step Synthesis of Chimeric Nutlin–DCA Compounds Targeting Dual Pathways for Treatment of Cancer

  2025cites this paper
• Dichloroacetate enhances Chemo-sensitivity in wild-type P53 breast cancer cells by modulating ABCG2 and NKG2DL

  2025cites this paper
• Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts

  2024cites this paper
• DR5 Up-Regulation Induced by Dichloroacetate Sensitizes Tumor Cells to Lipid Nanoparticles Decorated with TRAIL

  2023cites this paper
• A 15 Year Evolution of Dichloroacetate-Based Metabolic Cancer Therapy: A Review with Case Reports

  2023cites this paper
• Exosome secretion from hypoxic cancer cells reshapes the tumor microenvironment and mediates drug resistance

  2022cites this paper
• Oxidative Glucose Metabolism Promotes Senescence in Vascular Endothelial Cells

  2022cites this paper
• The metabolism of cells regulates their sensitivity to NK cells depending on p53 status

  2022cites this paper
• Effect of sodium dichloroacetate as single agent or in combination with cisplatin in normal and human cervical cancer cell lines

  2020cites this paper
• Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines

  2020cites this paper
• SLMP53-1 Inhibits Tumor Cell Growth through Regulation of Glucose Metabolism and Angiogenesis in a P53-Dependent Manner

  2020cites this paper
• TIGAR promotes growth, survival and metastasis through oxidation resistance and AKT activation in glioblastoma

  2019influential citation
• Mutations in the ND2 Subunit of Mitochondrial Complex I Are Sufficient to Confer Increased Tumorigenic and Metastatic Potential to Cancer Cells

  2019cites this paper
• The Role of Metabolic Plasticity in Blood and Brain Stem Cell Pathophysiology.

  2019cites this paper
• Sodium Dichloroacetate Pharmacological Effect as Related to Na–K–2Cl Cotransporter Inhibition in Rats

  2018cites this paper
• Natural Killer cell subsets in hematological diseases : learning for immunotherapy

  2018cites this paper
• Targeting Mitochondrial Bioenergetics as a Therapeutic Strategy for Chronic Lymphocytic Leukemia

  2018cites this paper
• Changes in metabolism affect expression of ABC transporters through ERK5 and depending on p53 status

  2017cites this paper
• MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer

  2017cites this paper
• The effect of dichloroacetate on male rat thymus and on thymocyte cell cycle

  2016cites this paper
• Design, Synthesis, and Biological Characterization of Novel Mitochondria Targeted Dichloroacetate-Loaded Compounds with Antileukemic Activity.

  2016cites this paper
• Metformin combined with sodium dichloroacetate promotes B leukemic cell death by suppressing anti-apoptotic protein Mcl-1

  2016cites this paper
• Ibrutinib synergizes with MDM-2 inhibitors in promoting cytotoxicity in B chronic lymphocytic leukemia

  2016cites this paper
• TARGETING LEUKEMIA CELL METABOLISM

  2015cites this paper
• The presence of wild type p53 in hematological cancers improves the efficacy of combinational therapy targeting metabolism

  2015cites this paper
• Dichloroacetate, a selective mitochondria-targeting drug for oral squamous cell carcinoma: a metabolic perspective of treatment

  2014cites this paper
• The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway

  2014cites this paper
• Dichloroacetate and cancer: new home for an orphan drug?

  2014cites this paper