Pro- and anticarcinogenic mechanisms of piceatannol are activated dose dependently in MCF-7 breast cancer cells.

Estrogenic procarcinogenic effects of piceatannol (PIC) contrast reports about anticarcinogenic activities of PIC. To explain this contradiction, we investigated PIC in estrogen-dependent MCF-7 breast cancer cells and elucidated those cellular mechanisms that correlated with the observed cell effects induced by PIC. Low PIC concentrations (50 nM) induced c-Myc that depended on progesterone receptor (PR) and estrogen receptor (ER). PR-mediated c-Myc induction by PIC was independent of nuclear PR activity but depended on mitogen-activated protein kinase (MAPK) signaling and was associated with an acceleration of cancer cell proliferation. In contrast, 25 µM PIC inhibited deoxynucleotide triphosphate synthesis, activated Chk2 and p38-MAPK and this was accompanied by an attenuation of cancer cell growth. Apoptosis was most probably inhibited due to activation of Akt; however, high PIC concentrations (>100 µM) permitted apoptosis-like cell death in consequence to disruption of orchestrated mitotic signaling. The presented results show for the first time that nanomolar PIC concentrations signal through PR and Erk1/2 and provide a mechanistic explanation why moderate wine consumption-but not other alcoholic beverages-increases the breast cancer risk in women. In contrast, higher PIC concentrations in the micromolar range are considered for adjuvant anticancer therapeutic concepts.

Involvement of Mrp2 (Abcc2) in biliary excretion of moxifloxacin and its metabolites in the isolated perfused rat liver.

Moxifloxacin is a novel antibacterial agent that undergoes extensive metabolism in the liver to the glucuronide M1 and the sulfate M2, which are eliminated via the bile. To investigate the role of the multidrug resistance-associated protein (Mrp2) as the hepatic transport system for moxifloxacin and its conjugates, livers of Wistar and Mrp2-deficient TR- rats were perfused with moxifloxacin (10 microM) in a single-pass system. Values for the hepatic extraction ratio (E) and clearance (Cl) were insignificantly higher in TR- rats than Wistar rats (0.193+/-0.050 vs 0.245+/-0.050 for E; 6.85+/-1.96 vs 8.73+/-1.82 mL min(-1) for Cl), whereas biliary excretion and efflux into perfusate over 60 min were significantly lower in the mutant rat strain. Cumulative biliary excretion of M1, M2 and moxifloxacin was significantly reduced to 0.027%, 19.1%, and 29.6% in the TR- rats compared with Wistar rats, indicating that the biliary elimination of M1 is mediated exclusively by Mrp2, whereas that of M2 and moxifloxacin seems to depend mostly on Mrp2 and, to a smaller extent, a further unidentified canalicular transporter. Moxifloxacin stimulates bile flow by up to 11% in Wistar rats, but not in TR- rats, further supporting an efficient transport of this drug and its glucuronidated and sulfated metabolites by Mrp2. Moxifloxacin (10 microM) also reversibly inhibited the Mrp2-mediated biliary elimination of bromsulphthalein in Wistar rats by 34%, indicating competition with the elimination of Mrp2-specific substrates. In conclusion, we found that Mrp2 mediates the biliary elimination of moxifloxacin and its glucuronidated and sulfated metabolites in rats. MRP2 may therefore play a key role in the transport of moxifloxacin and its conjugates into bile in humans.