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The calmodulin antagonist EBB reversal experimental study of tumor resistance

Author: ChengYanHong
Tutor: ZhuHuiFang
School: Peking Union Medical College , China
Course: Biochemistry and Molecular Biology
Keywords: Multidrug resistance Derivative of berbamine Reversal agent Calmodulin antagonist
CLC: R730.5
Type: Master's thesis
Year: 2006
Downloads: 108
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Abstract


Multidrug resistance （MDR） is a main impediment to the successful chemotherapy of cancers in clinic. Many efforts have been devoted to develop safe and effective reversal agents. In this study, we explored the reversal effect of 0-（4-ethoxiyl-butyl）-berbamine （EBB）, a derivative of bisbenzylisoqunoline alkaloid on P-glycoprotein （P-gp）-mediated multidrug resistant cells. （1） MTT assay were used to evaluate the cytotoxicity of EBB both in normal cells and a panel of human tumor cells in vitro. Results showed that EBB had no toxicity in ECV304 （a human umbilical vein endothelial cell line） and the IC50 values in tumor cells including four pairs of sensitive and multridrug resistant （MDR） tumor cells were from 4.55 to 15.74μM, indicating that MDR cells had not developed cross-resistance to EBB and it was not a substrate of P-glycoprotein （P-gp）. （2） IC50 values of doxorubicin （DOX） in MCF-7/ADR, MCF-7, K562/A02 and K562 were 128.6μM, 1.1μM, 206.3μM and 1.5μM respectively. EBB can significantly improve the chemo-sensitivity of P-gp-mediated multidrug resistant cells to DOX in MCF-7/DR and K562/A02 cells. Such effect of EBB was more potent than that of Verapamil （VPL） and can last more than 48h. （3） Various concentrations of EBB have no significant effect on the sensitivity of K562/G01 to Gleevec. （4）According to the method of Jin, analysis showed that EBB and DOX had synergistic effect on MCF-7/ADR, MCF-7, and K562/A02, K562 cells at lower dosage. （5） Flow cytometry analysis, Western blot, Immunoprecipitation, PI analysis, TUNEL analysis, DNA ladder and Confocal microsopy were used to explore the mechanisms involved in the reversal activity of EBB. Then we got the following results: （1）EBB can inhibit the effux function of P-gp which is encoded by the MDR1 gene, but have no effect on its protein expression, the level of MDR1 gene and another MDR related gene TopoIIb. （2）MDR cells had developed resistance to apoptosis caused by DOX. In addition, levels of Ca2+ in MDR cells

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CLC: > Medicine, health > Oncology > General issues > Tumor Therapy
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