HDAC inhibitor

HDACs’ expression is often deregulated in cancers, neurological diseases and immune disorders. The first reports about aberrant chromatin acetylation in cancer were described for a subtype of acute myeloid leukaemia with a recurrent translocation t and for acute promyelocytic leukaemia with the t translocation generating the PML-RARa protein fusion. However, there is minimal definitive experimental evidence that HDAC overexpression is oncogenic except for HDAC2 that may have a functional role in colorectal tumorigenesis. Indeed, inhibition of HDAC1, HDAC2, or HDAC3 may in certain circumstances be tumour promoting. Aberrant HDAC expression and function lead to neuropathology: learning and memory dysfunction, neurodegenerative and neurological diseases (like Alzheimer’s disease and Parkinson’s disease, respectively), neuronal development, depression and anxiety. HDACs are target for cancer treatment in leukaemia’s and myelodysplastic syndromes. Many clinical trials are ongoing for solid tumours. However clinical results have been often disappointing. A better selection of tumours and patients is necessary to benefit from these treatments; only tumours where HDACs are directly involved might respond better. Interestingly, combination of HDAC and DNMT inhibitors when used at low doses and during a short period was reported to be more efficient than single treatments and improved the effect of a conventional anticancer agent in NSCLC (non-small cell lung carcinoma) patients. Several studies were developed to combine HDAC inhibitors with other epigenetic targets. For example, combined treatment with JQ1 (an inhibitor of BET proteins that recognized acetylated histones) and SAHA was synergistic to suppress pancreatic and lung adenocarcinoma in specific mouse models. Thus, this strategy seems promising and may be rapidly implemented in poor prognostic human tumours.

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