Synergy between proteasome inhibitors and imatinib mesylate in chronic myeloid leukemia.
BACKGROUND
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.


RESULTS
We 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 beta-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 NFkappaB.


CONCLUSIONS
These data suggest that combined use of tyrosine kinase inhibitor and proteasome inhibitor might be helpful for optimizing CML treatment.
Hu
Zheng
Z
Laboratory of Molecular Target-Based Therapy for Cancer, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Pan
Xiao-Fen
XF
Wu
Fu-Qun
FQ
Ma
Li-Yuan
LY
Liu
Da-Peng
DP
Liu
Ying
Y
Feng
Ting-Ting
TT
Meng
Fan-Yi
FY
Liu
Xiao-Li
XL
Jiang
Qian-Li
QL
Chen
Xiao-Qin
XQ
Liu
Jing-Lei
JL
Liu
Ping
P
Chen
Zhu
Z
Chen
Sai-Juan
SJ
Zhou
Guang-Biao
GB
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010879:Piperazines / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D061988:Proteasome Inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D034622:RNA Interference
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate