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Histone deacetylase inhibitors specifically kill nonproliferating tumour cells

Oncogene volume 23, pages 6693–6701 (2004)Cite this article

Abstract

Conventional chemotherapeutic drugs target proliferating cells, relying on often small differences in drug sensitivity of tumour cells compared to normal tissue to deliver a therapeutic benefit. Consequently, they have significant limiting toxicities and greatly reduced efficacy against nonproliferating compared to rapidly proliferating tumour cells. This lack of selectivity and inability to kill nonproliferating cells that exist in tumours with a low mitotic index are major failings of these drugs. A relatively new class of anticancer drugs, the histone deacetylase inhibitors (HDI), are selectively cytotoxic, killing tumour and immortalized cells but normal tissue appears resistant. Treatment of tumour cells with these drugs causes both G1 phase cell cycle arrest correlated with increase p21 expression, and cell death, but even the G1 arrested cells died although the onset of death was delayed. We have extended these observations using cells that were stably arrested by either serum starvation or expression of the cyclin-dependent kinase inhibitor p16ink4a. We report that histone deacetylase inhibitors have similar cytotoxicity towards both proliferating and arrested tumour and immortalized cells, although the onset of apoptosis is delayed by 24 h in the arrested cells. Both proliferating and arrested normal cells are unaffected by HDI treatment. Thus, the histone deacetylase inhibitors are a class of anticancer drugs that have the desirable features of being tumour-selective cytotoxic drugs that are equally effective in killing proliferating and nonproliferating tumour cells and immortalized cells. These drugs have enormous potential for the treatment of not only rapidly proliferating tumours, but tumours with a low mitotic index.

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Acknowledgements

This work was supported by grants from the NHMRC of Australia to BG, RJ and NS.

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Authors and Affiliations

  1. Cancer Biology Program, Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Brisbane, 4102, Queensland, Australia

    Andrew Burgess, Heather Beamish, Robyn Warrener, Nicholas Saunders & Brian Gabrielli

  2. Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia

    Astrid Ruefli & Ricky Johnstone

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  1. Andrew Burgess
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  2. Astrid Ruefli
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Correspondence to Brian Gabrielli.

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Burgess, A., Ruefli, A., Beamish, H. et al. Histone deacetylase inhibitors specifically kill nonproliferating tumour cells. Oncogene 23, 6693–6701 (2004). https://doi.org/10.1038/sj.onc.1207893

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