Finding the place of histone deacetylase inhibitors in prostate cancer therapy

Abstract

Histone deacetylase inhibitors (HDACIs) are showing promise as therapeutic agents for hematological malignancies and solid tumors. In the case of prostate cancer, HDACIs are effective at inhibiting proliferation and inducing apoptosis in a range of in vitro and in vivo experimental models. Recent studies have revealed that the actions of HDACIs in prostate cancer cells extend beyond regulation of histone acetylation and affect proteins involved in maintaining cellular homeostasis and tumor progression, including the androgen receptor, p21^WAF1 and VEGF. The broad spectrum of HDACI targets has allowed rational design of combinations with other therapeutic agents to target multiple pathways involved in prostate cancer progression, including angiogenesis and androgen signaling. In particular, synergistic inhibition of prostate cancer cell growth has been demonstrated using HDACIs in combination with radio- and chemo-therapy, Apo2L/TRAIL, angiogenesis inhibitors, heat-shock protein 90 inhibitors and androgen receptor antagonists. This review examines the current understanding of the actions of HDACIs in prostate cancer cells, both in a laboratory and a clinical context and discusses the potential utility of combination strategies for the treatment of prostate cancer.

Keywords::

• androgen signaling
• clinical trials
• combination therapies
• histone deacetylase inhibitors
• prostate cancer

Acknowledgments

The authors thank Tina Bianco-Miotto for helpful discussions on the manuscript.

Financial & competing interests disclosure

This work was funded by the National Health and Medical Research Council of Australia (453662, to Wayne D Tilley and Lisa M Butler) and the US Army Medical Research and Materiel Command (W81XWH-04-1-0017, to Wayne D Tilley and Lisa M Butler). Deborah L Marrocco-Tallarigo and Margaret M Centenera were recipients of University of Adelaide Postgraduate Awards. Lisa M Butler holds a Cancer Council of South Australia Senior Research Fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.