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

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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.