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

P-糖蛋白（P-gp）的过度表达通常在癌细胞中观察到，已被证明是肿瘤多药耐药的主要因素。基于其结构可充当P-gp底物的膳食类黄酮可反过来影响药物转运出细胞，从而导致与抗肿瘤治疗功效增加相关的化疗药物的细胞积累增加。在结肠癌的APCmin/f小鼠模型中发现了X\PC基因的功能缺失突变，并且在绝大多数散发性人类结肠癌中也有代表，这与P-gp表达增加相关。我们在此提出了一项研究，该研究评估了经典化疗药物在APCmitV+小鼠模型中与显示与P-gp相互作用的黄酮类化合物共同给药时的促凋亡潜力。在初始筛选中使用人肠结肠癌细胞（Caco-2细胞），确定抗肿瘤药物拓扑替康和P-gp抑制类黄酮单独或组合对细胞凋亡的剂量依赖性作用。将证明具有最高增强作用的组合转移到动物模型中，并测试其对肿瘤细胞凋亡和腺瘤发展的作用。

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.