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

Chiara Agnoletto, Elisabetta Melloni, Fabio Casciano, Gian Matteo Rigolin, Erika Rimondi, Claudio Celeghini, Laura Brunelli, Antonio Cuneo, Paola Secchiero, Giorgio Zauli

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4347-4360
Number of pages14
JournalOncotarget
Volume5
Issue number12
Publication statusPublished - 2014

Keywords

  • B-CLL
  • Nutlin-3
  • p21
  • Sodium dichloroacetate

ASJC Scopus subject areas

  • Oncology
  • Medicine(all)

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