Synergistic interactions between PLK1 and HDAC inhibitors in non-Hodgkin’s lymphoma cells occur in vitro and in vivo and proceed through multiple mechanisms
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Tri Nguyen1, Rebecca Parker1, Elisa Hawkins1, Beata Holkova1, Victor Yazbeck1, Akhil Kolluri1, Maciej Kmieciak5, Mohamed Rahmani1 and Steven Grant1,2,3,4,5
1Division of Hematology/Oncology, Department of Internal Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA, USA
2Departments of Biochemistry, Virginia Commonwealth University, Richmond, VA, USA
3Departments of Pharmacology, Virginia Commonwealth University, Richmond, VA, USA
4Virginia Institute for Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA
5Massey Cancer Center, Virginia Commonwealth University Health Sciences Center, Richmond, VA, USA
Steven Grant, email: email@example.com
Keywords: non-Hodgkin’s lymphoma, volasertib, belinostat
Received: August 17, 2016 Accepted: November 22, 2016 Published: February 23, 2017
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.
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