Synergistic interactions between PLK1 and HDAC inhibitors in non-Hodgkin’s lymphoma cells occur in vitro and in vivo and proceed through multiple mechanisms

// Tri Nguyen 1 , Rebecca Parker 1 , Elisa Hawkins 1 , Beata Holkova 1 , Victor Yazbeck 1 , Akhil Kolluri 1 , Maciej Kmieciak 5 , Mohamed Rahmani 1 and Steven Grant 1, 2, 3, 4, 5 1 Division of Hematology/Oncology, Department of Internal Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA, USA 2 Departments of Biochemistry, Virginia Commonwealth University, Richmond, VA, USA 3 Departments of Pharmacology, Virginia Commonwealth University, Richmond, VA, USA 4 Virginia Institute for Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA 5 Massey Cancer Center, Virginia Commonwealth University Health Sciences Center, Richmond, VA, USA Correspondence to: Steven Grant, email: steven.grant@vcuhealth.org Keywords: non-Hodgkin’s lymphoma, volasertib, belinostat Received: August 17, 2016     Accepted: November 22, 2016     Published: February 23, 2017 ABSTRACT Interactions between the polo-like kinase 1 (PLK1) inhibitor volasertib and the histone deacetylase inhibitor (HDACI) belinostat were examined in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells in vitro and in vivo. Exposure of DLBCL cells to very low concentrations of volasertib in combination with belinostat synergistically increased cell death (apoptosis). Similar interactions occurred in GC-, ABC-, double-hit DLBCL cells, MCL cells, bortezomib-resistant cells and primary lymphoma cells. Co-exposure to volasertib/belinostat induced a marked increase in M-phase arrest, phospho-histone H3, mitotic errors, cell death in M-phase, and DNA damage. Belinostat diminished c-Myc mRNA and protein expression, an effect significantly enhanced by volasertib co-exposure. c-Myc knock-down increased DNA damage and cell death in response to volasertib, arguing that c-Myc down-regulation plays a functional role in the lethality of this regimen. Notably, PLK1 knock-down in DLBCL cells significantly increased belinostat-induced M-phase accumulation, phospho-histone H3, γH2AX, and cell death. Co-administration of volasertib and belinostat dramatically reduced tumor growth in an ABC-DLBCL flank model (U2932) and a systemic double-hit lymphoma model (OCI-Ly18), accompanied by a pronounced increase in survival without significant weight loss or other toxicities. Together, these findings indicate that PLK1/HDAC inhibition warrants attention as a therapeutic strategy in NHL.