Abstract
Rituximab/chemotherapy relapsed and refractory B cell lymphoma patients have a poor overall prognosis, and it is urgent to develop novel drugs for improving the therapy outcomes. Here, we examined the therapeutic effects of chidamide, a new histone deacetylase (HDAC) inhibitor, on the cell and mouse models of rituximab/chemotherapy resistant B-cell lymphoma. In Raji-4RH/RL-4RH cells, the rituximab/chemotherapy resistant B-cell lymphoma cell lines (RRCL), chidamide treatment induced growth inhibition and G0/G1 cell cycle arrest. The primary B-cell lymphoma cells from Rituximab/chemotherapy relapsed patients were sensitive to chidamide. Interestingly, chidamide triggered the cell death with the activation of autophagy in RRCLs, likely due to the lack of the pro-apoptotic proteins. Based on the RNA-seq and chromatin immunoprecipitation (ChIP) analysis, we identified BTG1 and FOXO1 as chidamide target genes, which control the autophagy and the cell cycle, respectively. Moreover, the combination of chidamide with the chemotherapy drug cisplatin increased growth inhibition on the RRCL in a synergistic manner, and significantly reduced the tumor burden of a mouse lymphoma model established with engraftment of RRCL. Taken together, these results provide a theoretic and mechanistic basis for further evaluation of the chidamide-based treatment in rituximab/chemotherapy relapsed and refractory B-cell lymphoma patients.
Highlights
The standard first-line treatment for patients with diffuse large B-cell lymphoma (DLBCL) is rituximab combined with chemotherapy, which leads to an around 60% complete remission rate
It is worth testing the therapeutic efficacy of a novel histone deacetylase (HDAC) inhibitor, chidamide, in the rituximab/ chemotherapy resistant B-cell lymphoma cell lines (RRCLs)-derived cell/mouse model, which will be helpful for the future clinical application of HDAC inhibitor in the treatment of relapsed/refractory B-cell lymphoma
Patient #1 was a 57-year-old man who had become resistant from 6 times rituximab plus CHOP treatment; patient #2 was a 63-year-old man who was diagnosed as non-hodgkin’s lymphoma; patient #3 was a DLBCL patient who had relapsed from 3 times rituximab plus CHOP treatment
Summary
The standard first-line treatment for patients with diffuse large B-cell lymphoma (DLBCL) is rituximab combined with chemotherapy, which leads to an around 60% complete remission rate. Despite overall improvements in the clinical outcomes of DLBCL, approximately one-third of patients still develop relapsed/refractory disease. The clinical approach to relapsed/refractory DLBCL include high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT). Given the deficiencies of the proapoptotic proteins, the therapeutic strategy targeting the autophagy pathway could be effective in the rituximab/chemotherapy relapsed and refractory B-cell lymphoma. It is worth testing the therapeutic efficacy of a novel histone deacetylase (HDAC) inhibitor, chidamide, in the RRCL-derived cell/mouse model, which will be helpful for the future clinical application of HDAC inhibitor in the treatment of relapsed/refractory B-cell lymphoma
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