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. 2009 Apr;30(4):451-7.
doi: 10.1038/aps.2009.19. Epub 2009 Mar 9.

Berbamine exhibits potent antitumor effects on imatinib-resistant CML cells in vitro and in vivo

Yan-lin Wei  1 , Lei Xu, Yun Liang, Xiao-hua Xu, Xiao-ying Zhao
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"VSports app下载" Berbamine exhibits potent antitumor effects on imatinib-resistant CML cells in vitro and in vivo

Yan-lin Wei et al. Acta Pharmacol Sin. 2009 Apr.

Abstract

Aim: The aim of this study was to explore the effects and mechanism of berbamine on imatinib-resistant BCR-ABL-positive human leukemia K562 (K562-r) cells in vitro and in vivo VSports手机版. .

Methods: Cell viability was measured by MTT assay, and apoptotic morphology changes were detected by fluorescence microscopy. The apoptosis rate was measured by flow cytometric assay. mdr-1 mRNA levels were determined by RT-PCR. Bcl-2 family proteins, cytochrome c(cyt C), poly (ADP-ribose) polymerase (PARP), and P-glycoprotein were detected by Western blot. BALB/c nu/nu mice were injected with K562-r cells subcutaneously. Tumor-bearing mice were treated intravenously with berbamine V体育安卓版. .

Results: MTT tests revealed that berbamine significantly inhibited K562-r cell proliferation and increased the chemo-sensitivity of K562-r cells to imatinib. The apoptosis rate was significantly increased following treatment with 21. 2 micromol/L berbamine; formation of typical apoptotic blebs was apparent, as observed by fluorescence microscopy. Expression levels of mdr-1 mRNA and P-gp protein were high in untreated K562-r cells and significantly down-regulated by berbamine treatment. Berbamine-treated K562-r cells also exhibited down-regulated expression of the anti-apoptotic proteins Bcl-2 and Bcl-x(L), up-regulated expression of the apoptotic proteins Bax and cytoplasmic cyt C, and stimulated proteolytic cleavage of PARP. In addition, berbamine also suppressed the growth of K562-r xenotransplanted tumors in vivo V体育ios版. .

Conclusion: Berbamine inhibited proliferation of K562-r cells both in vitro and in vivo. Berbamine-induced apoptosis in K562-r cells appeared to occur through a mechanism involving Bcl-2 family proteins, as well as mdr-1 mRNA and P-gp protein. Berbamine in combination with imatinib restored the chemo-sensitivity of K562-r cells to imatinib. Our findings suggest that berbamine may be useful in treating imatinib-resistant CML patients. VSports最新版本.

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Figures (V体育ios版)

Figure 1
Figure 1
Apoptotic effects of berbamine on K562-r cells. (A) Effects of berbamine on K562-r cell growth. Cells were incubated with different concentrations of berbamine, and the total number of viable cells was determined by MTT assay at 24 h and 48 h after treatment. (B) Effects of imatinib with or without 5.3 μmol/L berbamine on K562-r cell growth for 48 h. (C) Fluorescence photomicrographs of cells stained with Hoechst 33258 (400×). (Left panel) control; (right panel) K562-r cells treated with 21.2 μmol/L berbamine for 24 h. (D) Fluorescence-activated sorting analysis of annexin-V-FITC/PI for quantification of berbamine-induced apoptosis in K562-r cells treated with 21.2 μmol/L berbamine for 0, 6, 12, or 24 h. Error bars represent SD.
Figure 2
Figure 2
K562-r cells were exposed to berbamine at 21.2 μmol/L for different time periods and Bcl-2, Bax, Bcl-xL, PARP, total cyt C, cytoplasmic cyt C, and P-glycoprotein levels (A, B, C, D, E,) were determined by Western blot. mdr-1 mRNA levels (F) were determined by RT-PCR. β-actin was used as a loading control.
Figure 3
Figure 3
Effect of berbemine on the growth of K562-r cells in vivo. Berbamine was administered iv at 60 mg/kg body weight in two daily injections (8:00 and 16:00) 24 h after the subcutaneous injection of 5×107 K562-r cells. Control mice were treated with equivalent volumes of saline instead of drug. Each experimental group contained six mice. Tumor volume at d 30, both (A) and (B); (C) liver and spleen HE staining. Results are presented as average tumor volume (D); error bars represent 95% confidence intervals and are displayed only when they exceed 5% of the respective mean.
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