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Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway

An Erratum to this article was published on 01 February 2005

Abstract

Histone deacetylases (HDACs) regulate transcription and specific cellular functions, such as tumor suppression by p53, and are frequently altered in cancer1,2,3,4. Inhibitors of HDACs (HDACIs) possess antitumor activity and are well tolerated, supporting the idea that their use might develop as a specific strategy for cancer treatment. The molecular basis for their selective antitumor activity is, however, unknown. We investigated the effects of HDACIs on leukemias expressing the PML-RAR or AML1-ETO oncoproteins, known to initiate leukemogenesis through deregulation of HDACs. Here we report that: (i) HDACIs induce apoptosis of leukemic blasts, although oncogene expression is not sufficient to confer HDACI sensitivity to normal cells; (ii) apoptosis is p53 independent and depends, both in vitro and in vivo, upon activation of the death receptor pathway (TRAIL and Fas signaling pathways); (iii) TRAIL, DR5, FasL and Fas are upregulated by HDACIs in the leukemic cells, but not in normal hematopoietic progenitors. These results show that sensitivity to HDACIs in leukemias is a property of the fully transformed phenotype and depends on activation of a specific death pathway.

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Figure 1: VPA increases survival of APL mice and induces selective apoptosis of the leukemia blasts.
Figure 2: VPA upregulates TRAIL, DR5, FasL and Fas in APL cells in vivo and in vitro.
Figure 3: Activation of TRAIL and Fas cause VPA-induced APL cell death.
Figure 4: Biological effects of VPA or TSA on non-APL myeloid leukemias.

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Acknowledgements

We thank E. Grassilli, M. Faretta, F. Padula, R. Fiorini and D. Croci for discussions. This work was supported by grants from European Community (QLG1-CT-2001-01935), Ministero dell' Istruzione, dell'Universita' e della Ricerca and Associazione Italiana per la Ricerca sul Cancro to P.G.P. and S.M., and from Fondazione Monzino to P.G.P.

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Correspondence to Saverio Minucci or Pier Giuseppe Pelicci.

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Supplementary information

Supplementary Fig. 1

VPA has no apoptotic effect on normal and preleukemic cells. (PDF 79 kb)

Supplementary Fig. 2

Effects of HDAC-i in vivo and dose-response in vitro. (PDF 125 kb)

Supplementary Fig. 3

VPA induces apoptosis and expression of TRAIL and Fas in blasts from t(15;17) and t(8;21) patients. (PDF 58 kb)

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Insinga, A., Monestiroli, S., Ronzoni, S. et al. Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat Med 11, 71–76 (2005). https://doi.org/10.1038/nm1160

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