Gambogic acid induces apoptosis in diffuse large B-cell lymphoma cells via inducing proteasome inhibition.

Xianping Shi,Jinbao Liu,Xiaoying Lan,Hongbiao Huang,Yuning Liao,Chong Zhao,Dan Zang,Xin Chen,Peiquan Zhang,Xiaofen Li,Shouting Liu,Ningning Liu,Xuejun Wang

doi:10.1038/srep09694

Abstract

Resistance to chemotherapy is a great challenge to improving the survival of patients with diffuse large B-cell lymphoma (DLBCL), especially those with activated B-cell-like DLBCL (ABC-DLBCL). Therefore it is urgent to search for novel agents for the treatment of DLBCL. Gambogic acid (GA), a small molecule derived from Chinese herb gamboges, has been approved for Phase II clinical trial for cancer therapy by Chinese FDA. In the present study, we investigated the effect of GA on cell survival and apoptosis in DLBCL cells including both GCB- and ABC-DLBCL cells. We found that GA induced growth inhibition and apoptosis of both GCB- and ABC-DLBCL cells in vitro and in vivo, which is associated with proteasome malfunction. These findings provide significant pre-clinical evidence for potential usage of GA in DLBCL therapy particularly in ABC-DLBCL treatment.

Highlights

Resistance to chemotherapy is a great challenge to improving the survival of patients with diffuse large B-cell lymphoma (DLBCL), especially those with activated B-cell-like DLBCL (ABC-DLBCL)
We found that Gambogic acid (GA) induced growth inhibition and apoptosis of both GCB- and ABC-DLBCL cells in vitro and in vivo, which is associated with proteasome malfunction
To investigate the effect of GA on the growth of DLBCL cells, SU-DHL-4 and SU-DHL-2 cells were treated with GA in vitro for 48 hours and cell viability was detected by MTS assay

Summary

Introduction

Resistance to chemotherapy is a great challenge to improving the survival of patients with diffuse large B-cell lymphoma (DLBCL), especially those with activated B-cell-like DLBCL (ABC-DLBCL). We found that GA induced growth inhibition and apoptosis of both GCB- and ABC-DLBCL cells in vitro and in vivo, which is associated with proteasome malfunction These findings provide significant pre-clinical evidence for potential usage of GA in DLBCL therapy in ABC-DLBCL treatment. There are three subcategories in DLBCL: activated B-cell-like DLBCL (ABC-DLBCL), germinal center B-cell-like DLBCL (GCB-DLBCL) and primary mediastinal DLBCL (PMBCL)[2,3] These subtypes are characterized by distinct differences in survival, chemoresponsiveness, as well as dependence on signaling pathways, especially the nuclear factor-kB (NF-kB) pathway. We have reported that GA is a novel tissue-specific proteasome inhibitor, with potency comparable to bortezomib but much less toxicity[19] Proteasome inhibitors such as carfilzomib have been reported to induce cell death in DLBCL cells combining with HDAC (histone deacetylase) inhibitors[20], the effect of GA on DLBCL remains unknown. GA displays pronounced antineoplastic activity in both GCB- and ABC-DLBCL cells and in in vivo DLBCL xenograft models

Methods

Results

Conclusion