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Histone deacetylase inhibitors have antitumor activity in two NOD/SCID mouse models of B-cell precursor childhood acute lymphoblastic leukemia

Leukemia volume 20, pages 1435–1436 (2006)Cite this article

Histone deacetylase inhibitors (HDACI) induce maturation, proliferation arrest and apoptosis of a wide variety of cancer cells, including leukemia, but are apparently non-toxic to normal cells.1 Thus, several of these compounds are currently being evaluated in clinical trials, and first results are promising. Regarding acute lymphoblastic leukemia (ALL) of childhood, there is only limited in vitro data currently available regarding the proapoptotic effect of HDACI.2, 3 Importantly, the in vivo therapeutic potential of HDACI in lymphoblastic leukemia has not yet been evaluated.

We determined the therapeutic potential of three hydroxamic acid-HDACI (Vorinostat, CBHA, Pyroxamide) and of one short-chain fatty acid-HDACI (VPA) in three B-cell precursor (BCP)-ALL cell lines (Reh, Nalm6, Z33) in vitro and in two non-obese diabetes/severe combined immunodeficiency (NOD/SCID) mouse models of childhood ALL in vivo. In vitro, all HDACI showed a dose- and time-dependent proliferation inhibition MTS (3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium) assay), induction of apoptosis (annexin/propidium iodide staining, flow cytometry) and histone H4 hyperacetylation (Western blot). The calculated IC50 (inhibitor concentration resulting in 50% non vital cells) after 96 h of HDACI incubation were in the 0–10 μ M range (2–6 μ M) for Vorinostat, Pyroxamide and CBHA, and in the 0.1–1 mM range (0.5–0.9 mM) for VPA (data not shown). These data are in accordance with those of others who found similar apoptosis-inducing concentrations of the HDACI Vorinostat and VPA in BCP-ALL cell lines,3, 4 suggesting that the proapoptotic effect of HDACI generally applies to BCP-ALL cell lines rather than being cell line specific. In T-cell ALL, the proapoptotic activity of several HDACI belonging to different classes (Butyrate, Trichostatin A, Vorinostat) was demonstrated previously.2 Taken together, there is concordant evidence for the fact that HDACI are capable of inducing apoptosis in a wide variety of T- and BCP-ALL cell lines, providing a strong rationale for evaluation of these substances in preclinical models of ALL.

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Acknowledgements

We gratefully acknowledge S Shalapour for technical help with Western blotting and L Badiali for performing initial flow cytometry assays. This work was supported by a grant of Kind-Philipp-Stiftung für Leukämieforschung e.V. (to LK) and a grant of Deutsche José Carreras Leukämie-Stiftung e.V. (to HGE; DJCLS R 05/18).

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  1. H Graf Einsiedel and L Kawan: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany

    H Graf Einsiedel, L Kawan, C Eckert, G Henze & K Seeger

  2. Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    O Witt

  3. Max-Delbrück – Center for Molecular Medicine, Experimental Pharmacology, Berlin, Germany

    I Fichtner

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  1. H Graf Einsiedel
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Correspondence to H Graf Einsiedel.

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Einsiedel, H., Kawan, L., Eckert, C. et al. Histone deacetylase inhibitors have antitumor activity in two NOD/SCID mouse models of B-cell precursor childhood acute lymphoblastic leukemia. Leukemia 20, 1435–1436 (2006). https://doi.org/10.1038/sj.leu.2404282

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