Berbamine: a novel inhibitor of bcr/abl fusion gene with potent anti-leukemia activity.
Gleevec, which is an inhibitor of the bcr/abl tyrosine kinase, has been a remarkable success for the treatment of chronic myelogenous leukemia (CML). However, a significant proportion of patients chronically treated with Gleevec develop resistance. Here we describe the activity of a natural small molecular compound, berbamine from plant Berberis amurensis that can selectively induce cell death of both Gleevec-sensitive and -resistant Ph+ CML cells. The IC50 values of berbamine were 8.80 microg/ml in Gleevec-sensitive Ph+ CML cells, 11.34 microg/ml in Gleevec-resistant Ph+ CML cells, and 54.40 microg/ml in Ph- KG-1 cells, respectively. Similarly, berbamine was also found to display a selective anti-proliferative activity of primary leukemia cells from CML patients, and its IC50 values were 4.20-10.50 microg/ml in primary CML cells, and 185.20 microg/ml in normal bone marrow cells, respectively. More importantly, our studies demonstrate that berbamine down-regulates p210bcr/abl oncoprotein level, and induces apoptosis of bcr/abl+ cells through caspase-3-dependent pathway. These data suggest that berbamine might be a novel bcr/abl inhibitor with potent anti-leukemia activity.
Xu
Rongzhen
R
Department of Hematology, Second Affiliated Hospital, Hangzhou, Zhejiang Province 310009,China. zrxyk10@zju.edu.cn
Dong
Qinghua
Q
Yu
Yingzi
Y
Zhao
Xiaoying
X
Gan
Xiaoxian
X
Wu
Dong
D
Lu
Qinghua
Q
Xu
Xiaohua
X
Yu
Xiao-Fang
XF
D000470:Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D044182:Benzylisoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use
D000470:Alkaloids; D001549:Benzamides; D044182:Benzylisoquinolines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C027870:berbamine