Understanding Mechanisms of Histone Deacetylase Inhibitors in Regulating Growth and Survival in Aggressive Diffuse Large B-Cell Lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and commonly-diagnosed form of non-Hodgkin lymphoma. Under the current standard of treatment, R-CHOP, 40% of patients are refractory or relapse, and need further therapeutic intervention. Histone deacetylases (HDACs) have a large role in cancer cell survival and can be targeted therapeutically for cancer treatment with combination treatments. However, efficient use of HDACi in combination treatments is hindered by a poor understanding of their mechanisms of action. To address this, we developed a pre-clinical model system of sensitivity and resistance to the Class I and Class IIb pan-HDACi, belinostat, using DLBCL cell lines. Cell lines sensitive to belinostat undergo mitotic arrest, followed by apoptosis. Cells resistant to belinostat arrest in G1. Forced mitotic arrest in HDACi-resistant cell lines with a microtubule targeting agent, vincristine, in combination with belinostat caused synergistic cytotoxicity associated with downregulated expression of anti-apoptotic factor MCL-1 and upregulated pro-apoptotic factor BIM. Vincristine-induced cellular polyploidy was also eliminated by belinostat. Additionally, inhibition of just Class I HDACs is sufficient for synergistic apoptosis with vincristine, and reduces polyploidy. Our results suggest that all class I HDAC-containing complexes must be targeted to observe maximal cytotoxicity in combination with vincristine in resistant cell lines.