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.
Highlights
Non-Hodgkin’s lymphoma (NHL) is a lymphoproliferative neoplasm that afflicts approximately 70,000 patients/year in the US, and is responsible for 20,000 deaths [1]
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
Volasertib dose-response studies in GC-DLBCL SU-DHL4 cells revealed that concentrations as low as 12 nM significantly increased the lethal effects of 300-500 nM belinostat, with higher concentrations (e.g., 25 nM) sharply increasing cell death (Figure 1C)
Summary
Non-Hodgkin’s lymphoma (NHL) is a lymphoproliferative neoplasm that afflicts approximately 70,000 patients/year in the US, and is responsible for 20,000 deaths [1]. Molecular profiling has identified genetic NHL signatures which predict poor prognoses e.g., double-hit lymphomas displaying aberrant expression of Bcl-2, c-Myc, and/or Bcl-6 [2]. Despite recent advances such as the introduction of effective new targeted therapies for this disease (e.g., Ibrutinib) [3], patients with relapsed/refractory disease have a dismal prognosis [4]. Disruption of PLK1 function triggers multiple mitotic abnormalities, including aberrant mono-polar spindles, anaphase bridging, and arrest of cells in pro-metaphase (“Polo arrest”) accompanied by up-regulation of phospho-histone H3 and apoptosis [10, 11]. Experience with volasertib in DLBCL or other aggressive forms of NHL in general is lacking
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