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

迷迭香提取物抑制多药耐药中 P-糖蛋白介导的药物流出

• 批准号: 6289050
• 负责人: GRACE YEH
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289050
• 关键词: MCF7 cell; P glycoprotein; antioxidants; chemoprevention; doxorubicin; exocytosis; multidrug resistance; mutagen testing; phenols; plant extracts; tissue /cell culture; transfection

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,

原标题：正常大鼠胎盘组织和细胞中多药耐药性的激素调节常用香料和调味剂迷迭香，源自植物 Rosmarinus officinalis L. 的叶子，具有重要的抗氧化活性。尽管鼠尾草酚、鼠尾草酸、迷迭香二酚、迷迭香醇、异迷迭香醇、表罗斯曼醇和迷迭香醌是迷迭香叶中的抗氧化化合物[Nakatani, N. in: Huang et al. 2017]。 （编辑），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酚和鼠尾草酸 [Aruoma 等人，2017]。 （1932）异生素 22：257-268]。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) 流出的物质 [Critchfield 等人，2017]。 (1994)生物化学。医药。 48：1437-1445]。我们研究了迷迭香对人乳腺癌耐药细胞化疗药物流出机制的影响。迷迭香提取物经过部分纯化，并通过艾姆斯试验评估其抗氧化活性。研究了迷迭香在 MCF-7 野生型 (WT)、耐药亚克隆 R65 和 MDR1 转染（克隆 10.9）MCF-7 细胞中的作用。有趣的是，我们发现迷迭香提取物过量 330 倍或 1000 倍时会竞争 P-gp 的叠氮平标记。我们进一步证明，迷迭香显着降低了 P-gp 表达 R65 和克隆 10.9 细胞中的 P-gp Adr 外流，但对 WT MCF-7 细胞没有影响。迷迭香提取物的细胞毒性作用极低，WT 和 R65 细胞中的 IC50 分别为 125 mM 和 150 mM。这是首次证明迷迭香等天然产物可以抑制 P-gp 介导的药物外流。我们的研究结果表明，迷迭香可以作为癌症化疗的 MDR 逆转剂。该项目已停止。 - 阿霉素、乳房、鼠尾草酚、MCF-7、迷迭香、