植物天然产物逆转多重耐药。

Reversal of multidrug resitance by natural substances from plants.

机构信息

Institute of Medical Microbiology and Immunobiology, University of Szeged, H-6720 Szeged, Dóm tér 10. Hungary.

出版信息

Curr Top Med Chem. 2010;10(17):1757-68. doi: 10.2174/156802610792928103.

PMID:20645919

Abstract

The multidrug resistance (MDR) proteins that belong to the ATP-binding cassette superfamily such as P-glycoprotein (P-gp) and MRP1, are present in a majority of human tumors and constitute an important cause of therapeutic failure. Selective inhibitors of the MDR-efflux proteins may improve the effectiveness of cancer chemotherapy. Their mechanism of action was believed to be a competition between resistance modifiers and drugs for the same binding site of P-gp. In our previous work we studied modulation of MDR in cancer cells expressing P-gp or MRP1 by selected carotenoids, flavonoids and extracts from medically important Chinese plants. Capsanthin and capsorubin, carotenoids isolated from paprika, were identified as potent P-gp inhibitors, while lycopene, lutein, antheraxanthin and violaxanthin induced moderate effects. Among flavonoids, effective modulators were rotenone, chrysin, phloretin and sakuranetin. Some chloroform extracts of Chinese herbs were also found to inhibit MDR efflux pumps. The effects of the modulators on P-gp activity were studied by measuring rhodamine 123 uptake in several cancer cells such as the human MDR1 gene-transfected mouse lymphoma cells (L1210) and human breast cancer cells MDA-MB-231 expressing the MRP1 pump (HTB26). Additionally, the ability to alter biophysical properties of lipid bilayers by selected carotenoids was studied by differential scanning calorimetry. The antiproliferative effects as well as the MDR reversal activity of the studied compounds, applied in combination with anticancer drugs, were also discussed.

摘要

多药耐药（MDR）蛋白属于 ATP 结合盒超家族，如 P-糖蛋白（P-gp）和 MRP1，存在于大多数人类肿瘤中，是治疗失败的重要原因。MDR 外排蛋白的选择性抑制剂可能提高癌症化疗的效果。它们的作用机制被认为是耐药调节剂和药物之间在 P-gp 的相同结合位点上的竞争。在我们之前的工作中，我们研究了选择的类胡萝卜素、类黄酮和来自重要药用植物的提取物对表达 P-gp 或 MRP1 的癌细胞的 MDR 调节作用。从红辣椒中分离出的辣椒红素和辣椒玉红素被鉴定为有效的 P-gp 抑制剂，而番茄红素、叶黄素、玉米黄质和矢车菊黄素则诱导适度的作用。在类黄酮中，有效的调节剂是鱼藤酮、白杨素、根皮素和樱花素。一些来自中国草药的氯仿提取物也被发现能抑制 MDR 外排泵。通过测量几种癌细胞（如转染人 MDR1 基因的小鼠淋巴瘤细胞（L1210）和表达 MRP1 泵的人乳腺癌细胞 MDA-MB-231）摄取罗丹明 123，研究调节剂对 P-gp 活性的影响。此外，还通过差示扫描量热法研究了选择的类胡萝卜素改变脂质双层生物物理性质的能力。还讨论了研究化合物的抗增殖作用以及与抗癌药物联合应用的 MDR 逆转活性。