Enhancing the apoptotic and therapeutic effects of HDAC inhibitors
Section snippets
Anti-cancer effects of HDACi
HDACi can induce diverse biological responses in tumour cells including induction of apoptosis, and suppression of cell proliferation by activation of cell cycle checkpoints at G1/S or G2/M [1]. Moreover, the ability of HDACi to suppress angiogenesis and activate and enhance the host immune system may play important indirect roles in their therapeutic response [1]. It is currently unclear which one or more of these biological effects are necessary for the anti-cancer responses attributed to
HDACi induce apoptotic tumor cell death
HDACi are potent inducers of tumor cell apoptosis that can be mediated by regulating histone function and subsequently gene transcription, and/or by regulating the function or stability of non-histone proteins (Fig. 1). While induction of apoptosis appears to be the predominant mechanism of HDACi-mediated cell death, alternative cell death mechanisms such as autophagy may be stimulated when apoptotic proteins or pathways are disabled although the molecular events required for HDACi-mediated
Enhanced tumor cell apoptosis using HDACi in combination with other anti-cancer agents
HDACi clearly have single agent anti-tumor activity in experimental mouse models of cancer and in the clinic. However, as detailed below, these agents also have the capacity to synergise with a range of other anti-cancer agents.
Summary
HDACi are promising anti-cancer agents and indeed vorinostat has been approved by the FDA for the treatment of cutaneous T cell lymphoma [55]. In pre-clinical models, a clear link between direct tumor cell killing and therapeutic efficacy has been established and these agents are very potent inducers of tumor cell apoptosis. As monotherapies, HDACi have thus far been shown to be effective against a defined subset of haematological tumors and induce moderate and largely manageable side effects
Acknowledgments
We apologise to those whose work was not cited or discussed due to space limitations. We thank members of the Johnstone laboratory for helpful discussions. Ricky Johnstone is a Pfizer Australia Research Fellow and is supported by the National Health and Medical Research Council of Australia, the Cancer Council Victoria, the Leukaemia Foundation of Australia and by research grants from Novartis and Merck. Ailsa Frew and Jessica Bolden are supported by The Cancer Research Institute Predoctoral
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These authors contributed equally to this manuscript.