Impact of P-Glyoprotein inhibition by flavonoids on topotecan-induced apoptosis in intestinal tumors of APCmin/+ mice
Zusammenfassung der Projektergebnisse
ATP-driven efflux pumps such as phosphoglycoprotein-170 (P-gp) play a crucial role in limiting the efficacy of tumor pharmacotherapy. Selected flavonoids have been suggested to inhibit individual efflux-transporters and to act therefore as multidrugresistance reversing agents. Our studies show that the flavonoids flavone and chrysin act as potent inhibitors of P-gp transport activity but on the other hand increase the expression of P-gp, even in the presence of the tumor therapeutic topotecan. Although both compounds were able to increase the accumulation of the anti-tumor drug in Caco-2 cells they potently inhibited topotecan-induced apoptosis, suggesting that anti-apoptotic effects are generated by P-gp. On a molecular basis the stabilisation of the transcription factor ß-catenin was found to be associated with the inhibiton of apoptosis. Similar accumulation of ß-catenin in the cytosol could be observed in vivo in adenomas of APCmin/+ mice, which were increased in numbers by flavone. According to previous results showing that P-gp can be induced by flavone in the small intestine but not in the large intestine it is suggested that the induction of P-gp by flavone is, at least in part, responsible for the observed cancer promoting effect of flavone in the small intestine. In the large intestines of APCmin/+ mice an increase in apoptosis was caused by flavone. As the P-gp inducing activity of flavone does not prevail in the large intestine, probably due to a maximal expression rate, anti-apoptotic actions of P-gp appear to be absent allowing flavone to exert still apoptotic effects. In conclusion, flavone is recognized by intestinal epithelial cells as a xenobiotic, stimulating the expression of xenobiotic efflux pumps. This provides anti-apoptotic mechanisms in the small intestine where P-gp expression is rather low but not in the large intestine where the absence of P-gp inducing activities might allow apoptotic effects of flavone to prevail.
Projektbezogene Publikationen (Auswahl)
- Flavonoids alter P-gp expression in intestinal epithelial cells in vitro and in vivo. Mol. Nutr. Food Res. 51: 293-300 (2007)
Lohner, K., Schnäbele, K., Daniel, H., Oesterle, D., Rechkemmer, G., Göttlicher, M., Wenzel, U.
