Chronic myeloid leukemia (CML) is a pluripotent hematopoietic stem cell disorder characterized by accumulation of mature and immature granulocytes in peripheral blood and bone marrow due to uncontrolled growth and resistance to apoptosis. The dysregulated activity of the bcr/abl oncoprotein tyrosine kinase, which is encoded by the bcr?abl fusion gene, has been shown to be responsible for the malignant phenotypes.
Gleevec, which is an inhibitor of the bcr/abl tyrosine kinase, has been a remarkable success for the treatment of CML. However, a significant proportion of patients chronically treated with Gleevec develop resistance. Thus, new approaches that override the resistance are crucial to the development of curative therapies for CML.A recent study, to be published in Leukemia Research (available online 14 July 2005) describes the anti-leukemia 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.
Importantly, the results in this study show that berbamine is also active against Gleevec-resistant leukemia cells. It is of interest to note that berbamine down-regulates p210 bcr/abl oncoprotein of Ph+ leukemia cells, suggesting that this compound have different anti-leukemia mechanism from that of Gleevec.
The results indicate that up to 76% of leukemia cells were apoptotic cells after treatment with berbamine at concentration of 16 ì g/ml for 48 h, suggesting that the growth inhibition of berbamine for leukemia cells is caused by apoptosis of leukemia cells. Results also suggest that berbamine-induced apoptosis is mediated via caspase-3-dependent pathway.
Another important feature of berbamine is the very desirable safety that is not often seen in conventional chemotherapeutic agents. In addition, berbamine is widely used to improve normal hematopoiesis and immune function of cancer patients in China.
The authors conclude that berbamine might be a novel bcr/abl inhibitor with potent anti-leukemia activity, and that the potency of berbamine against both Gleevec-sensitive and -resistant Ph+ leukemia cells, and its distinct mechanism of anti-leukemia activity warrant further investigation of berbamine for the treatment of CML.
