Anthracyclines, proteasome activity and multi-drug-resistance
Anthracyclines, proteasome activity and multi-drug-resistance
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DOI：
10.1186/1471-2407-5-114
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发表时间：
2005-09-13
期刊：
影响因子：
3.8
通讯作者：
Pajonk, F
中科院分区：
文献类型：
--
作者：
Fekete, MR;McBride, WH;Pajonk, F
背景资料：P-糖蛋白负责某些结构上不相关的化合物（包括许多化疗药物）的ATP依赖性输出。P-糖蛋白活性的扩增可导致多药耐药，并且是化疗治疗失败的常见原因。因此，目前正在寻找P-糖蛋白的抑制剂。观察到环孢菌素A和某些其他物质同时抑制蛋白酶体和P-糖蛋白，这使我们研究了蒽环类药物（众所周知的P-gp底物）是否也抑制蛋白酶体的功能。在来自ECV 304细胞的细胞裂解物中测量蛋白酶体功能，所述ECV 304细胞与不同剂量的维拉帕米、多柔比星、柔红霉素、伊达比星、表柔比星、拓扑替康、丝裂霉素C，和吉西他滨。使用用泛素/绿色荧光蛋白融合蛋白的基因稳定转染的ECV 304细胞监测活细胞中的蛋白酶体功能。蛋白酶体抑制剂MG-132影响P-糖蛋白功能的能力进行了监测，由于在P-糖蛋白过度表达KB 8-5 cells.Results：维拉帕米，柔红霉素，阿霉素，依达罗肽，和epirrandine的积累荧光抑制26 S糜蛋白酶样功能ECV 304提取物中的剂量依赖性的方式。除柔红霉素外，20 S蛋白酶体功能也受到抑制。蛋白酶体抑制剂MG-132引起柔红霉素在KB 8-5细胞中的剂量依赖性蓄积，该细胞过度表达P-糖蛋白，表明其阻断P-糖蛋白function.Conclusion：我们的数据表明，蒽环类药物抑制26 S蛋白酶体以及P-糖蛋白。在癌症治疗中使用任一途径的抑制剂应考虑到这一点，并可能利用它的优势，例如在蛋白酶体抑制剂的化学增敏过程中。
Background: P-glycoprotein is responsible for the ATP-dependent export of certain structurally unrelated compounds including many chemotherapeutic drugs. Amplification of P-glycoprotein activity can result in multi-drug resistance and is a common cause of chemotherapy treatment failure. Therefore, there is an ongoing search for inhibitors of P-glycoprotein. Observations that cyclosporin A, and certain other substances, inhibit both the proteasome and P-glycoprotein led us to investigate whether anthracyclines, well known substrates of P-gp, also inhibit the function of the proteasome.Methods: Proteasome function was measured in cell lysates from ECV304 cells incubated with different doses of verapamil, doxorubicin, daunorubicin, idarubicin, epirubicin, topotecan, mitomycin C, and gemcitabine using a fluorogenic peptide assay. Proteasome function in living cells was monitored using ECV304 cells stably transfected with the gene for an ubiquitin/green fluorescent protein fusion protein. The ability of the proteasome inhibitor MG-132 to affect P-glycoprotein function was monitored by fluorescence due to accumulation of daunorubicin in P-glycoprotein overexpressing KB 8-5 cells.Results: Verapamil, daunorubicin, doxorubicin, idarubicin, and epirubicin inhibited 26S chymotrypsin-like function in ECV304 extracts in a dose-dependent fashion. With the exception of daunorubicin, 20S proteasome function was also suppressed. The proteasome inhibitor MG-132 caused a dose-dependent accumulation of daunorubicin in KB 8-5 cells that overexpress P-glycoprotein, suggesting that it blocked P-glycoprotein function.Conclusion: Our data indicate that anthracyclines inhibit the 26S proteasome as well as P-glycoprotein. Use of inhibitors of either pathway in cancer therapy should take this into consideration and perhaps use it to advantage, for example during chemosensitization by proteasome inhibitors.