During imatinib therapy, many patients with chronic myeloid leukemia (CML) develop severe neutropenia, leading to treatment interruptions, and potentially compromising response to imatinib. Berbamine (a bisbenzylisoquinoline alkaloid) has been widely used in Asian countries for managing leukopenia associated with chemotherapy. To investigate whether berbamine shows clinical benefit in reversing imatinib-associated neutropenia, we analyzed 63 chronic-phase CML patients who had developed grade ?2 neutropenia and were treated with (n = 34, berbamine group) or without (n = 29, control group) berbamine. Among those patients with grade 2 neutropenia, five of 13 (38.5%) progressed to grade 3 neutropenia without berbamine support, while in the berbamine group, the rate decreased to 3/20 (15%) (p = 0.213). Although the rate of recovery from grade ?3 neutropenia was similar in the two groups (94.1 vs. 90.5%, p = 0.559), berbamine markedly shortened the recovery time (median, 11 vs. 24 days, p = 0.006), and prevented recurrence of grade ?3 neutropenia (18.8 vs. 52.6%, p = 0.039). Moreover, with berbamine support, the time to achieve complete cytogenetic response was significantly shorter (median, 6.5 vs. 10 months, p = 0.007). There were no severe adverse events associated with berbamine treatment. In conclusion, the present study reveals the potential clinical value of berbamine in the treatment of CML with imatinib-induced neutropenia. The use of berbamine may improve response to imatinib by stimulating normal hematopoiesis and faster neutropenia recovery.
Berbamine overcomes imatinib-induced neutropenia and permits cytogenetic responses in Chinese patients with chronic-phase chronic myeloid leukemia
Posted 14 July 2011 - 11:17 PM
The antiproliferation effect of berbamine on k562 resistant cells by inhibiting NF-kappaB pathway.
Department of Hematology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
Imatinib mesylate is effective against Ph chromosome-positive leukemia; however, resistance has been reported. High expression of bcr-abl in mRNA and protein levels, and other alterations were found in patients who experienced imatinib treatment failures and thus it is important to design alternative treatment strategies. The aim of this study was to evaluate the in vitro effect of berbamine, on imatinib-resistant chronic myelogenous leukemia (CML) K562 (K562-r) cells, and explore the mechanisms. The growth of K562-r cells was examined using the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Morphological analysis and DNA agarose electrophoresis were used to detect apoptosis in K562-r cells, and the extent of the cells in the sub-G1 cell cycle phase was measured using flow cytometry. The expression levels of BCR-ABL, phospho-BCR-ABL, and nuclear factor kappaB (NF-kappaB), IkappaBalpha, phospho-IkappaBalpha, IkappaB kinases alpha(IKKalpha), and Survivin were determined by Western blot. bcr-abl mRNA expression was determined by RT-PCR. MTT assays indicated that berbamine significantly inhibited the proliferation of K562-r cells. Cells with characteristics of apoptosis were confirmed by morphology examination and DNA agarose electrophoresis and percentage of apoptosis were increased after treatment with berbamine. The results also showed that berbamine was able to down-regulate BCR-ABL and phospho-BCR-ABL proteins by affecting bcr-abl mRNA expression and decrease expression of nuclear NF-kappaB, phospho-IkappaBalpha, IKKalpha, and Survivin. Collectively, berbamine could inhibit the proliferation of K562-r cells and induce apoptosis. The mechanisms may be related at least in part, to inhibit BCR-ABL and its downstream NF-kappaB signaling. Berbamine may provide an alternative candidate for the treatment of patients with CML resistant to imatinib therapy.
- [PubMed - indexed for MEDLINE]
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