Vorinostat synergizes with Antioxidant therapy to target Myeloproliferative Neoplasms

Abstract The BCR-ABL-negative myeloproliferative neoplasms (MPN) are driven by JAK-STAT pathway activation but epigenetic alterations also play an important pathophysiological role. These can be pharmacologically manipulated with histone deacetylase inhibitors (HDACis), which have proven to be clinically effective in the treatment of MPN but exhibiting dose-limiting toxicities. The treatment of primary MPN cells with Vorinostat modulates the expression of genes associated with apoptosis, cell cycle, inflammation and signalling. The induction of this transcriptional program results a decreased cellular viability, paralleled by a decrease in Reactive Oxygen Species (ROS) levels. In vitro manipulation of ROS levels showed that the reduction of ROS levels promoted apoptosis. When Vorinostat was combined with anti-oxidant agents, the apoptosis of MPN cells was increased in a synergistic manner. The results described here suggest a novel and promising therapeutic strategy to treat MPN combining HDACis with ROS reducing agents.