Histone Deacetylase Inhibitors Induce Growth Inhibition, Cell Cycle Arrest and Apoptosis in Mantle Cell Lymphoma and Reduce VEGF Production.

Mantle cell lymphoma (MCL) is a B cell lymphoma characterized by the translocation t(11;14)(q13;q32) and an overexpression of cyclin D1. Since current therapy regimens are not effective enough, novel treatment strategies are urgently needed. Histone deacetylase (HDAC) inhibitors have emerged as a new group of agents effective in several human malignancies. This study evaluated the effects of HDAC inhibitors on mantle cell lymphoma.

Three human mantle cell lymphoma cell lines (JeKo-1, Hbl-2 and Granta-519) were exposed to different concentrations of the HDAC inhibitors sodium butyrate and SAHA. MTT assays showed a reduced survival of cells after exposure to these agents. After 48 hours of incubation, IC50 of viability was noted at 1.0μM in JeKo-1, at 3.9μM in Hbl-2 and at 4.3μM in Granta-519. For sodium butyrate, IC50 was observed approximately at 1.5mM in JeKo-1, 1.9mM in Hbl-2 and 11.2mM in Granta-519 after 48 hours. Annexin-V staining showed that all of the SAHA and sodium butyrate-treated cell lines underwent specific apoptosis in a time and dose dependent manner. Cell cycle analysis revealed a decreased proportion of cells in S phase and increased proportion of cells in the G0/G1 and/or G2/M phases after treatment with HDAC inhibitors. To evaluate the effects of HDAC inhibitors on cell cycle regulators, the protein levels of p21, p27, and cyclin D1 were analyzed. SAHA increased p21 in all three cell lines. Expression of p27 was enhanced in JeKo-1 and Granta-519, while it remained constant in Hbl-2. Treatment with sodium butyrate increased the expression of p21 in JeKo-1 and Hbl-2, while in Granta-519 no effect was noted. The expression of p27 remained constant in all cell lines after exposure to sodium butyrate. Incubation of cells with both HDAC inhibitors lead to a downregulation of cyclin D1. In addition, we examined the influence of SAHA on the production of the angiogenic cytokine VEGF. Interestingly, treatment with SAHA led to a decrease of VEGF secretion in comparison to untreated cells. Based on these findings, we provide evidence that HDAC inhibitors have antiproliferative effects in mantle cell lymphoma and may represent a future therapeutic option for this disease.