Impact of P-Glyoprotein inhibition by flavonoids on topotecan-induced apoptosis in intestinal tumors of APCmin/+ mice

类黄酮抑制 P-糖蛋白对拓扑替康诱导的 APCmin/小鼠肠道肿瘤细胞凋亡的影响

• 批准号: 23241654
• 负责人: Professor Dr. Uwe Wenzel
• 金额: --
• 依托单位: Professur für Biochemie und Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/23241654?language=en
• 关键词: Impact; Glyoprotein; inhibition; flavonoids; topotecan

P-glycoprotein (P-gp) overexpression generally observed in cancer cells has proven to represent a major contributing factor to multi-drug-resistance of tumors. Dietary flavonoids which based on their structure can serve as P-gp substrates could in turn affect drug transport out of cells and thereby lead to an increased cellular accumulation of chemotherapeutics associated with an increased efficacy of antitumor therapy. A loss-of-function mutation in the X\PC-gene is found in the APCmin/f mice model of colon cancer and is also represented in the vast majority of sporadic human colon cancers and this is associated with an increased P-gp expression, We propose here a study that assesses the pro-apoptotic potential of classical chemotherapeutics in the APCmitV+ mouse model when those are co-administered with flavonoids shown to interact with P-gp. Using human intestinal colon cancer cells (Caco-2 cells) in an initial screen the dose-dependent effects of the anti-tumor drug topotecan and P-gp inhibiting flavonoids, either alone or in combination, on apoptosis will be determined. Combinations demonstrated to have the highest potentiating effect will be transferred into the animal model and are tested for their effects on apoptosis in tumors and the development of adenomas.

在肿瘤细胞中普遍观察到的P-糖蛋白(P-gp)过度表达是肿瘤多药耐药的主要因素。饮食中的类黄酮类化合物基于其结构可以作为P-gp底物，反过来可以影响药物向细胞外的转运，从而导致化疗药物在细胞内积累增加，从而提高抗肿瘤治疗的效果。在APCmin/f小鼠结肠癌模型中发现了X\PC-基因功能缺失突变，在绝大多数散发性人类结肠癌中也存在这种突变，这与P-gp表达增加有关。我们建议进行一项研究，评估经典化疗药物在APCmitV+小鼠模型中的促凋亡潜力，当这些药物与被证明与P-gp相互作用的黄酮类化合物联合使用时。使用人结肠癌细胞(Caco-2细胞)进行初步筛选，将确定抗肿瘤药物Topotecan和P-gp抑制黄酮类化合物单独或联合对细胞凋亡的剂量依赖效应。被证明具有最高增强效果的组合将被转移到动物模型中，并测试它们对肿瘤细胞凋亡和腺瘤发展的影响。