XX中药单体对肿瘤多药耐药的逆转作用及其机制研究

The present study discovers the mutidrug resistance (MDR) reversing activity of Chinese traditional medicine XX extract in vitro and in vivo, in which LC is the primary active component exhibiting MDR reversal action. XX extract and LC give significant reversal of resistance to vincristine, adriamycin and paclitaxel dose-dependently in a panel of required and innate MDR cell lines. The potency of XX extract and LC are much greater than that of verapamil, a classic MDR reversal agent. The ability of XX extract to reverse MDR in vivo is demonstrated using nude mice bearing KBv200 xenografts. XX extract itself also shows anticancer activity at higher doses without toxic effects. In the mechanism study, LC is found to increase the intracellular accumulation of anticancer drugs in MDR tumor cells through inhibiting the overexpression of P-glycorprotein at both mRNA and protein levels. Moreover, the reversal activity of LC may also be related to the increased susceptibility of MDR tumor cells to apoptosis induced by anticancer cells. The structure of LC are different from any of the classes of the known MDR reversal agents, and the source of XX is very rich in China. So XX extract and its active component LC may be developed as a MDR reversal agent, combined with anticancer drugs that are developed MDR by tumors easily to increase their anticancer activities, or developed as an anticancer agent. Now we are applying for the patent of XX and LC. Furthermore, we have found the MDR reversal activity of a drug which has been used in clinic in China for years. All of its reversal pharmacological tests are finished and its patent is under the authorization of Chinese Patent Bureau now. We also investigated the mechanism of required 5-FU resistance in Bel7402/5-FU cells. The results have been published in World Journal of gastroenterology.

肿瘤多药耐药（MDR）是肿瘤化疗失败的主要原因之一，研究MDR耐药的机制及寻找能逆转MDR的新药是国际上研究热点之一。我们新筛选到XX中药的一种单体LC及其粗提取物LCC在体舛远嘀种琢鱿赴闙DR有很强的逆转作用。LC在浓度为25uM时对VCR的逆转倍数可达300倍，而LC是一个与国内外现有的MDR逆转剂结构完全不同的天然成分。本项目拟围绕MDR的相关靶标，对LC及LCC逆转MDR作用的分子机制及其体内逆转肿瘤耐药的活性进行深入研究，以探讨LC及LCC本身作为新药开发的可能性。故本项目具有高度的原始创新性和我国自己的知识