The CXCR4 antagonist plerixafor enhances the effect of rituximab in diffuse large B-cell lymphoma cell lines

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.

MicroRNA‐9 inhibits growth and invasion of head and neck cancer cells and is a predictive biomarker of response to plerixafor, an inhibitor of its target CXCR4

“…To our knowledge, this is the first evidence of plerixafor affecting miR‐9‐mediated cellular functions. Usage of plerixafor has shown dramatic reduction in carcinogenic phenotype induced by CXCR4 in various in vitro cancer studies in solid tumours such as prostate and cervical cancers (Chaudary et al ., ; Conley‐LaComb et al ., ), as well as lymphomas (Reinholdt et al ., ). Plerixafor is already approved for the mobilisation of hematopoietic stem cells in lymphoma and multiple myeloma patients (Wagstaff, ).…”

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

“…Peled et al demonstrated that disrupting the CXCL12/CXCR4 axis using motixafortide is an effective way to abrogate the BM-derived mesenchymal stem-cell-mediated resistance of nHL cells to rituximab and to target nHL in the BM microenvironment [139]. Furthermore, plerixafor can enhance the effect of rituximab in DLBCL cell lines in vitro [140]. Previous studies have confirmed that abnormal activation of the PI3K/AKT/mTOR signaling pathway increases tumor proliferation and is associated with the poorer prognosis of patients with DLBCL [141].…”

A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models

“…[7][8][9] Thus, the CXCR4-CXCL12 axis is involved in tumor pathogenesis, cancer cell survival, stem cell phenotype, and resistance to chemotherapy. 10,11 In addition, CXCR4 is constitutively over-expressed in NHL cell lines, 12,13 and also in approximately 50% of malignant B-cell lymphocytes derived from DLBCL patients. 8 Interestingly, CXCR4 + DLBCL cell lines show resistance to rituximab but are sensitive to the combination of rituximab with a CXCR4 antagonist.…”