Significance: Epigenetic inactivation of pivotal genes involved in cell growth is a hallmark of human pathologies, in particular cancer. Histone acetylation balance obtained through opposing actions of HDACs and HATs is one epigenetic mechanism controlling gene expression and is thus associated with disease etiology and progression. Interfering pharmacologically with HDAC activity can correct abnormalities in cell proliferation, migration, vascularization and death. Recent advances: Histone deacetylase inhibitors (HDACi) represent a new class of cytostatic agents that interfere with the function of HDACs and are able to increase gene expression by indirectly inducing histone acetylation. Several HDACi, alone or in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, are currently in clinical trials for solid and haematological malignancies, and are thus promising candidates for cancer therapy. Critical issues: 1. Non-specific (off-target) HDACi effects due to activities unassociated with HDAC inhibition. 2. Advantages/disadvantages of non-selective or isoform-directed HDACi. 3. Limited number of response-predictive biomarkers. 4. Toxicity leading to dysfunction of critical biological processes. Future directions: Selective HDACi could achieve enhanced clinical utility by reducing or eliminating the serious side effects associated with current first-generation non-selective HDACi. Isoform-selective and pan-HDACi candidates might benefit from the identification of biomarkers allowing for better patient stratification and prediction of response to treatment.

Targeting HDACs in diseases: where are we?

Benedetti R;Conte M;ALTUCCI, Lucia
2014

Abstract

Significance: Epigenetic inactivation of pivotal genes involved in cell growth is a hallmark of human pathologies, in particular cancer. Histone acetylation balance obtained through opposing actions of HDACs and HATs is one epigenetic mechanism controlling gene expression and is thus associated with disease etiology and progression. Interfering pharmacologically with HDAC activity can correct abnormalities in cell proliferation, migration, vascularization and death. Recent advances: Histone deacetylase inhibitors (HDACi) represent a new class of cytostatic agents that interfere with the function of HDACs and are able to increase gene expression by indirectly inducing histone acetylation. Several HDACi, alone or in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, are currently in clinical trials for solid and haematological malignancies, and are thus promising candidates for cancer therapy. Critical issues: 1. Non-specific (off-target) HDACi effects due to activities unassociated with HDAC inhibition. 2. Advantages/disadvantages of non-selective or isoform-directed HDACi. 3. Limited number of response-predictive biomarkers. 4. Toxicity leading to dysfunction of critical biological processes. Future directions: Selective HDACi could achieve enhanced clinical utility by reducing or eliminating the serious side effects associated with current first-generation non-selective HDACi. Isoform-selective and pan-HDACi candidates might benefit from the identification of biomarkers allowing for better patient stratification and prediction of response to treatment.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11591/200495
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