Histone Deacetylase Inhibitors, Oxidative Stress, And Multiple Myeloma Therapy

Multiple myeloma (MM) is a hematologic malignancy characterized by dysregulated proliferation of plasma cells. Histone deacetylase (HDAC) inhibition results in the accumulation of acetylated nucleosomal histones and induces differentiation and apoptosis in transformed cells. HDAC inhibitors (HDACi) induce oxidative stress, DNA damage, and mitochondrial damage/dysfunction in myeloma cells. The release of apoptogenic factors from mitochondria leads to cell death. Synergistic antimyeloma activity of a combination regimen of HDACi with other agents was observed, in which increased oxidative stress plays a major role. A preclinical animal model also showed a strong inhibition of myeloma tumor growth and prolonged survival by KD5170 monotherapy. These findings indicate HDACi are promising anti-MM agents, mediated by gene modulation and induction of oxidative stress and subsequent apoptosis.