Abstract
BackgroundDiffuse large B-cell lymphoma (DLBCL) is an aggressive disease with variable clinical outcome, accounting for at least 25-30 % of adult non-Hodgkin lymphomas. Approximately one third of DLBCL patients are not cured by the currently used treatment regimen, R-CHOP. Hence, new treatment strategies are needed. Antagonizing the CXCR4 receptor might be promising since the CXCR4-CXCL12 axis is implicated in several aspects of tumor pathogenesis as well as in protection from chemotherapeutic response. In Burkitt lymphoma, the CXCR4 antagonist plerixafor has already been shown to enhance the therapeutic effect of rituximab, the immunotherapeutic agent of R-CHOP; but this is yet to be confirmed for DLBCL. We, therefore, investigated the effect of plerixafor on DLBCL cellular response to rituximab.MethodsIn this in vitro study, human DLBCL cell lines were treated with rituximab and/or plerixafor, concomitantly or in sequence. The trypan blue exclusion method and MTS-based assays were used to evaluate cellular proliferation, whereas flow cytometry was used for assessment of apoptosis status and CXCR4 surface expression level. Linear mixed effects models were used to assess statistical significance.ResultsWe observed that simultaneous addition of plerixafor and rituximab resulted in a significant decrease in DLBCL cellular proliferation, compared to monotherapeutic response. The effect was dose-dependent, and concomitant administration was observed to be superior to sequential drug administration. Accordingly, the fraction of apoptotic/dead cells significantly increased following addition of plerixafor to rituximab treatment. Furthermore, exposure of DLBCL cells to plerixafor resulted in a significant decrease in CXCR4 fluorescence intensity.ConclusionsBased on our results, implying that the anti-proliferative/pro-apoptotic effect of rituximab on DLBCL cells can be synergistically enhanced by the CXCR4 antagonist plerixafor, addition of plerixafor to the R-CHOP regimen can be suggested to improve treatment outcome for DLBCL patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s40364-016-0067-2) contains supplementary material, which is available to authorized users.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease with variable clinical outcome, accounting for at least 25-30 % of adult non-Hodgkin lymphomas
The C-X-C chemokine ligand type 12 (CXCR4) antagonist plerixafor significantly enhanced the rituximab-induced effect on growth inhibition of diffuse large B-cell lymphoma cell lines To determine if plerixafor modulates the effect of rituximab-induced growth inhibition, RIVA and FARAGE cells were treated with rituximab (10 μg/mL) and/or plerixafor (500 μM) for up to 72 h, and the number of living cells was counted by the trypan blue exclusion method, after 0 h, 24 h, and 72 h of drug exposure
We conclude that combination sequence of rituximab and plerixafor is of importance, with concomitant administration being superior to sequential administration
Summary
Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease with variable clinical outcome, accounting for at least 25-30 % of adult non-Hodgkin lymphomas. The treatment currently used for DLBCL is a multiagent regimen combining the anti-CD20 monoclonal antibody rituximab with three chemotherapeutic drugs, i.e. cyclophosphamide, doxorubicin, and vincristine, and with the corticosteroid prednisone (R-CHOP). 30-40 % of DLBCL patients have refractory disease or relapse after treatment with R-CHOP [7]. Relapsed patients are generally treated with high-dose chemotherapy in combination with autologous stem cell transplantation. The majority of these patients are, not eligible for this treatment strategy because of their age, comorbidities, or refractory disease. This subset of patients is not cured and, other therapeutic approaches are required.[8]
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