Abstract
BackgroundDiffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease and this variation can often be used to explain the response of individual patients to chemotherapy. One cancer therapeutic approach currently in clinical trials uses histone deacetylase inhibitors (HDACi’s) as monotherapy or in combination with other agents.Methodology/Principal FindingsWe have used a variety of cell-based and molecular/biochemical assays to show that two pan-HDAC inhibitors, trichostatin A and vorinostat, induce apoptosis in seven of eight human DLBCL cell lines. Consistent with previous reports implicating the BCL-2 family in regulating HDACi-induced apoptosis, ectopic over-expression of anti-apoptotic proteins BCL-2 and BCL-XL or pro-apoptotic protein BIM in these cell lines conferred further resistance or sensitivity, respectively, to HDACi treatment. Additionally, BCL-2 family antgonist ABT-737 increased the sensitivity of several DLBCL cell lines to vorinostat-induced apoptosis, including one cell line (SUDHL6) that is resistant to vorinostat alone. Moreover, two variants of the HDACi-sensitive SUDHL4 cell line that have decreased sensitivity to vorinostat showed up-regulation of BCL-2 family anti-apoptotic proteins such as BCL-XL and MCL-1, as well as decreased sensitivity to ABT-737. These results suggest that the regulation and overall balance of anti- to pro-apoptotic BCL-2 family protein expression is important in defining the sensitivity of DLBCL to HDACi-induced apoptosis. However, the sensitivity of DLBCL cell lines to HDACi treatment does not correlate with expression of any individual BCL-2 family member.Conclusions/SignificanceThese studies indicate that the sensitivity of DLBCL to treatment with HDACi’s is dependent on the complex regulation of BCL-2 family members and that BCL-2 antagonists may enhance the response of a subset of DLBCL patients to HDACi treatment.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma, accounting for 40% of non-Hodgkin lymphomas and 30% of all lymphomas [1]
We show that DLBCL cell lines can be made resistant to vorinostat, which may be useful in understanding the molecular mechanism by which patients develop resistance to HDACi treatment in the clinic
histone deacetylase inhibitors (HDACi’s) are currently being used to treat a variety of lymphomas and leukemias [5,6,7], and some of these studies, as well as the results we report here, indicate that the levels of pro- or anti-apoptotic BCL-2 family proteins may be important for determining sensitivity to HDACi treatment
Summary
Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma, accounting for 40% of non-Hodgkin lymphomas and 30% of all lymphomas [1]. One class of therapeutic agents currently in clinical trials includes epigenetic modifiers, mainly histone deacetylase inhibitors (HDACi’s) and DNA methyltrasferase inhibitors. Vorinostat was approved for treatment of T-cell lymphoma [10], and is currently in clinical trials for the treatment of a variety of B-cell lymphomas, showing promising results for certain advanced hematologic malignancies [11], but not for patients with relapsed DLBCL [10]. Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease and this variation can often be used to explain the response of individual patients to chemotherapy. One cancer therapeutic approach currently in clinical trials uses histone deacetylase inhibitors (HDACi’s) as monotherapy or in combination with other agents
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