Targeting Cancer and Neuropathy with Histone Deacetylase Inhibitors:Two Birds with One Stone?

V.      Rodriguez-Menendez; L.      Tremolizzo; G.      Cavaletti

Abstract

Histone deacetylase inhibitors (HDACi) belong to a novel class of drugs able to act on the epigenome, indirectly remodeling the spatial conformation of the chromatin: by increasing histone acetylation these drugs ultimately promote the detachment of the DNA from the nucleosome octamer, therefore allowing the access of transcription factors to the double helix. Such a mechanism of action is of particular interest in the field of cancer treatment, considering the reactivation of silenced tumor suppressor genes as an important target at which aiming; indeed, it is currently believed that dysregulation of the epigenome plays a major role in cancer. Interestingly, some of the compounds belonging to the HDACi family have also additional therapeutic properties, as in the case of valproate that may ameliorate neuropathic pain in animal models and in patients. Conceivably, this is a remarkable observation, since peripheral neuropathy is a potentially severe side effect of several classes of anticancer agents, such as platinum-derived drugs, antitubulins or protesome inhibitors, limiting an effective treatment of the underlying cancer. Based on these data, in this review we will argue that, with respect to other nowadays available anticancer agents, HDACi might offer the advantage not only to target the neoplastic disorder, but also to prevent peripheral neuropathies, possibly displaying a complementary mechanism of action.

Keywords: Cisplatin, neuropathy, cancer, histones, valproate, neuroprotection

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