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Acute Non-Lymphoblastic Leukemias

A novel retinoic/butyric hyaluronan ester for the treatment of acute promyelocytic leukemia: preliminary preclinical results

Leukemia volume 20, pages 785–792 (2006)Cite this article

Abstract

All-trans retinoic acid (ATRA) represents the therapy of choice for patients with acute promyelocytic leukemia (APL). However, patients often relapse due to ATRA-resistance. The molecular basis of APL alterations indicates that addition of a histone deacetylase inhibitor to ATRA may restore the sensitivity to retinoids. We explored the in vitro and in vivo effects of a novel retinoic/butyric hyaluronan ester (HBR) on a retinoic acid (RA)-sensitive human myeloid cell line, NB4, and on its RA-resistant subclone, NB4.007/6. In vitro, HBR induced growth arrest and terminal differentiation in RA-sensitive NB4 cells (as confirmed by an increased expression of CD11 family members and nitroblue tetrazolium assay), whereas it inhibited the growth of RA-resistant cells by apoptosis, paralleled by an increase in the levels of caspase 3 and 7. In vivo, HBR treatment of NB4-inoculated severe combined immunodeficient mice resulted in a statistically significant increase in survival time (P<0.0001), comparable to that induced by a maximum tolerated dose of RA alone. Also on P388-inoculated mice, HBR was active in contrast to RA that was completely ineffective. Present findings suggest that, owing to the simultaneous presence of RA and an histone deacetylases inhibitor, HBR might be useful in controlling the proliferation of RA-resistant cells and the differentiation of RA-sensitive cells.

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Acknowledgements

This work was supported in part by a grant from the Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MURST), Rome, Italy.

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Authors and Affiliations

  1. Experimental Department, Unit of Tumor Biology and Experimental Therapy, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy

    D Coradini, C Pellizzaro, G Abolafio, A Speranza, M Fedeli & M G Daidone

  2. Biochemistry, Biophysics and Chemistry of Macromolecules, University of Trieste, Trieste, Italy

    I Scarlata & S Cantoni

  3. Department of Biomedical Science, University of Trieste, Trieste, Italy

    S Zorzet, C Garrovo & G Sava

  4. Laboratory of Molecular Biology, National Institute of Biostructures and Biosystems, University of Bologna, Bologna, Italy

    I Scarlata & A Perbellini

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  1. D Coradini
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  2. C Pellizzaro
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  3. I Scarlata
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  4. S Zorzet
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  5. C Garrovo
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  6. G Abolafio
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  8. M Fedeli
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  9. S Cantoni
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  10. G Sava
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  11. M G Daidone
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  12. A Perbellini
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Corresponding author

Correspondence to D Coradini.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Coradini, D., Pellizzaro, C., Scarlata, I. et al. A novel retinoic/butyric hyaluronan ester for the treatment of acute promyelocytic leukemia: preliminary preclinical results. Leukemia 20, 785–792 (2006). https://doi.org/10.1038/sj.leu.2404179

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