ROSEMARY EXTRACT INHIBITS P-GLYCOPROTEIN MEDIATED DRUG EFFLUX IN MULTIDRUG-RESIST

原标题：正常大鼠胎盘组织和细胞多药耐药的激素调控常用的香料和调味剂迷迭香，从植物迷迭香的叶子中提取，具有重要的抗氧化活性。虽然鼠尾草醇、鼠尾草酸、迷迭香二酚、迷迭香醇、异迷迭香醇、表玫瑰醇和迷迭香醌是迷迭香叶中的抗氧化化合物[Nakatani， N. in: Huang等人主编，食品中的酚类化合物及其对健康的影响II：抗氧化剂和癌症预防，第72-86页]。华盛顿特区：美国化学学会，1992]迷迭香约90%的抗氧化活性可归因于鼠尾草醇和鼠尾草酸[Aruoma et al. (1932) Xenobiotic 22:7 7-268]。我们已经证明，其他抗氧化剂，如黄酮醇、槲皮素，是通过p -糖蛋白（P-gp）介导的机制有效刺激阿霉素（Adr）外排的刺激物[Critchfield et al. (1994) Biochem]。制药,48:1437 - 1445]。我们研究了迷迭香对人乳腺癌耐药细胞化疗药物外排机制的影响。对迷迭香提取物进行部分纯化，并采用Ames试验评价其抗氧化活性。研究了迷迭香对MCF-7野生型（WT）、耐药亚克隆R65和MDR1转染（克隆10.9）MCF-7细胞的影响。有趣的是，我们发现迷迭香提取物在330或1000倍过量时竞争P-gp的叠氮标签。我们进一步证明迷迭香能显著降低P-gp在R65和克隆10.9中的不良反应外排，但对WT MCF-7细胞没有影响。迷迭香提取物的细胞毒作用极低，分别在125 mM和150 mM的WT和R65细胞中观察到IC50。这是第一次发现像迷迭香这样的天然产物可以抑制P-gp介导的药物外排。我们的研究结果表明迷迭香可能作为癌症化疗的耐多药逆转剂。这个项目已经中止了。-阿霉素，Breast, carnosol, MCF-7，迷迭香，

Former title: Hormonal Regulation of Multidrug Resistance in Normal Rat Placental Tissues and Cells The commonly used spice and flavoring agent, rosemary, derived from the leaves of the plant Rosmarinus officinalis L. has important antioxidant activity. Although carnosol, carnosic acid, rosmaridiphenol, rosmanol, isorosmanol, epirosmanol, and rosmariquinone are antioxidant compounds in rosemary leaves [Nakatani, N. in: Huang et al. (eds), Phenolic compounds in Food and Their Effects on Health II: Antioxidants and Cancer Prevention, pp. 72-86. Washington, DC: American Chemical Society, 1992] about 90% of the antioxidant activity of rosemary can be attributed to carnosol and carnosic acid [Aruoma et al. (1932) Xenobiotic 22:257-268]. We have demonstrated that other antioxidants such as the flavonol, quercetin, are potent stimulators of adriamycin (Adr) efflux via a P-glycoprotein (P-gp)-mediated mechanism [Critchfield et al. (1994) Biochem. Pharm. 48:1437-1445]. We examined the the effect of rosemary in chemotherapeutic drug efflux mechanim in human breast cancer drug resistant cells. Rosemary extract was partially purified and the antioxidant activity evaluated by the Ames test. The effect of rosemary was studied in MCF-7 wild-type(WT), drug resistant subclone R65, and MDR1 transfected (Clone 10.9) MCF-7 cells. Interestingly, we found that rosemary extract when present in 330- or 1000-fold excess competed for azidopine labelling of P-gp. We further demonstrated that the rosemary markedly decreased the P-gp Adr efflux in P-gp expression R65 and Clone 10.9 but not WT MCF-7 cells. The cytotoxic effect of rosemary extract is extremely low as noted by the IC50 in WT and R65 cells of 125 mM and 150 mM,respectively. This is the first time that a natural product such as rosemary has been shown to inhibit P-gp mediated drug efflux. Our findings suggested that rosemary may serve as a MDR reversal agent for cancer chemotherapy. This project has been discontinued. - Adriamycin, Breast, carnosol, MCF-7, Rosemary,