Novel therapeutic approach in haematological malignancies: Combining histone deacetylase inhibitors with EZH2 targeting agents
Summary
Haematological malignancies are a clinically challenging and heterogeneous cluster of diseases that arise from hematopoietic cells with clonal proliferation. Recently, the synergistic sensitivity of haematological malignancies to a combination epigenetic therapy that includes targeting enhancer of Zeste homolog 2 (EZH2) through the drugs Tazemetostat and MS1943 and histone deacetylases (HDACs) through the drug Romidepsin was shown in peripheral T-cell lymphoma (PTCL) cell lines. However, it remains unclear whether this effect is universal for the HDAC inhibitors Belinostat, Panobinostat, and Vorinostat and a broad spectrum of haemato-oncological cell lines. Also, it remains unclear whether these drugs cause cell death through ferroptosis, necroptosis, or apoptosis. Through examining the effects of (a combination of) these drugs on cell viability, reactive oxygen species (ROS) formation, lipid peroxidation, and levels of the ferroptosis marker Acyl-CoA synthetase long-chain family member 4 (ACSL4) we will try to answer these questions. In line with previous research, synergy was found in the amount of cell death caused by the HDAC inhibitors Belinostat, Panobinostat, and Vorinostat in combination with the EZH2 targeting drugs MS1943 and Tazemetostat. Also, the HDAC inhibitor Romidepsin caused an increase in ROS formation and lipid peroxidation when combined with MS1943 and Tazemetostat. Furthermore, ferroptosis was found to be the most influential in causing cell death when combining Romidepsin with MS1943 or Tazemetostat. Our findings indicate that a broad spectrum of HDAC inhibitors have a synergistic effect with EZH2 targeting drugs in causing cell death and the main mechanism of cell death is ferroptosis.