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

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

Research output: Contribution to journalArticle

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 antileukemic 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.

Original languageEnglish
Pages (from-to)2385-2396
Number of pages12
JournalOncotarget
Volume6
Issue number4
Publication statusPublished - 2015

Fingerprint

Dichloroacetic Acid
Null Lymphocytes
B-Cell Chronic Lymphocytic Leukemia
Cell Line
Proteomics
Transfection
Mitochondria
Transcription Factors
Therapeutics
Cell Culture Techniques
Mutation
Survival

Keywords

  • B-CLL
  • Cytotoxicity
  • P21
  • Proteomics
  • Sodium dichloroacetate

ASJC Scopus subject areas

  • Oncology

Cite this

Agnoletto, C., Brunelli, L., Melloni, E., Pastorelli, R., Casciano, F., Rimondi, E., ... Zauli, G. (2015). The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway. Oncotarget, 6(4), 2385-2396.

The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway. / Agnoletto, Chiara; Brunelli, Laura; Melloni, Elisabetta; Pastorelli, Roberta; Casciano, Fabio; Rimondi, Erika; Rigolin, Gian Matteo; Cuneo, Antonio; Secchiero, Paola; Zauli, Giorgio.

In: Oncotarget, Vol. 6, No. 4, 2015, p. 2385-2396.

Research output: Contribution to journalArticle

Agnoletto, C, Brunelli, L, Melloni, E, Pastorelli, R, Casciano, F, Rimondi, E, Rigolin, GM, Cuneo, A, Secchiero, P & Zauli, G 2015, 'The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway', Oncotarget, vol. 6, no. 4, pp. 2385-2396.
Agnoletto, Chiara ; Brunelli, Laura ; Melloni, Elisabetta ; Pastorelli, Roberta ; Casciano, Fabio ; Rimondi, Erika ; Rigolin, Gian Matteo ; Cuneo, Antonio ; Secchiero, Paola ; Zauli, Giorgio. / The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway. In: Oncotarget. 2015 ; Vol. 6, No. 4. pp. 2385-2396.
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