Synergy between Proteasome Inhibitors and Imatinib Mesylate in Chronic Myeloid Leukemia

Zheng Hu,Xiao-Li Liu,Zhu Chen,Ying Liu,Sai-Juan Chen,Ting-Ting Feng,Jing-Lei Liu,Qian-Li Jiang,Fan-Yi Meng,Li-Yuan Ma,Guang-Biao Zhou,Xiao-Fen Pan,Ping Liu,Fu-Qun Wu,Xiao-Qin Chen,Da-Peng Liu,Ulrich Zanger

doi:10.1371/journal.pone.0006257

Abstract

BackgroundResistance developed by leukemic cells, unsatisfactory efficacy on patients with chronic myeloid leukemia (CML) at accelerated and blastic phases, and potential cardiotoxity, have been limitations for imatinib mesylate (IM) in treating CML. Whether low dose IM in combination with agents of distinct but related mechanisms could be one of the strategies to overcome these concerns warrants careful investigation.Methods and FindingsWe tested the therapeutic efficacies as well as adverse effects of low dose IM in combination with proteasome inhibitor, Bortezomib (BOR) or proteasome inhibitor I (PSI), in two CML murine models, and investigated possible mechanisms of action on CML cells. Our results demonstrated that low dose IM in combination with BOR exerted satisfactory efficacy in prolongation of life span and inhibition of tumor growth in mice, and did not cause cardiotoxicity or body weight loss. Consistently, BOR and PSI enhanced IM-induced inhibition of long-term clonogenic activity and short-term cell growth of CML stem/progenitor cells, and potentiated IM-caused inhibition of proliferation and induction of apoptosis of BCR-ABL+ cells. IM/BOR and IM/PSI inhibited Bcl-2, increased cytoplasmic cytochrome C, and activated caspases. While exerting suppressive effects on BCR-ABL, E2F1, and β-catenin, IM/BOR and IM/PSI inhibited proteasomal degradation of protein phosphatase 2A (PP2A), leading to a re-activation of this important negative regulator of BCR-ABL. In addition, both combination therapties inhibited Bruton's tyrosine kinase via suppression of NFκB.ConclusionThese data suggest that combined use of tyrosine kinase inhibitor and proteasome inhibitor might be helpful for optimizing CML treatment.

Highlights

Imatinib mesylate (IM)/Gleevec/STI571, a rationally-designed agent that occupies the ATP-binding site of BCR-ABL and stabilizes the protein in its inactive conformation, has been a remarkable success for the treatment of chronic myeloid leukemia (CML)[1,2,3,4]
These data suggest that combined use of tyrosine kinase inhibitor and proteasome inhibitor might be helpful for optimizing CML treatment
To infect bone marrow cells, 2 ml infectious cocktail which mixed retroviral supernatant and DMEM culture media supplemented with 8 mg/mL polybrene, 7 ng/ml recombinant IL-3, 12 ng/ml rmIL-6, 56 ng/ml rm stem cell factor (SCF), 15% fetal bovine serum (FBS) and 5% supernatant of WEHI-3B cells was added to 16106 cells in a 6-well plate

Summary

Introduction

Imatinib mesylate (IM)/Gleevec/STI571, a rationally-designed agent that occupies the ATP-binding site of BCR-ABL and stabilizes the protein in its inactive conformation, has been a remarkable success for the treatment of chronic myeloid leukemia (CML)[1,2,3,4]. Optimization of treatment for CML still warrants investigation because a proportion of patients develop IM-resistance[5,6,7,8], and patients with CML at accelerated phase (AP) or blastic crisis (BC) often respond unsatisfactorily [9,10,11]. Resistance developed by leukemic cells, unsatisfactory efficacy on patients with chronic myeloid leukemia (CML) at accelerated and blastic phases, and potential cardiotoxity, have been limitations for imatinib mesylate (IM) in treating CML. Whether low dose IM in combination with agents of distinct but related mechanisms could be one of the strategies to overcome these concerns warrants careful investigation

Methods

Results

Discussion

Conclusion