Effects of the proteasome inhibitor @entity1749 on apoptosis and angiogenesis in orthotopic XXXX @entity788 xenografts.

@entity1 @entity788 @entity522 @entity2451 @entity39 @entity5 @entity7 @entity1749
Recent studies have shown that the transcription factor, nuclear factor @entity2451 ( @entity2451 ), regulates critical survival pathways in a variety of different cell types, including @entity1 @entity788 cells. The activation of @entity2451 is controlled by proteasome-mediated degradation of its endogenous polypeptide inhibitor, inhibitor of nuclear factor kappaBalpha. We investigated the effects of @entity1749 , a peptide boronate inhibitor of the proteasome in @entity1 @entity788 cells in vitro and in vivo. Comparison of @entity1749 's effects on the growth of eight different @entity1 @entity788 cell lines revealed marked heterogeneity in drug responsiveness, ranging from highly resistant (IC50 > 10 microM; Panc-48, HS766T, and Mia-PaCa-2) to extremely sensitive (IC50 < 40 nM; L3.6pl, Hpaf2, and BxPC3). However, these effects did not correlate with differential inhibition of @entity2451 activation. Direct quantification of apoptosis revealed that @entity1749 's effects on cell growth largely correlated with sensitivity to programmed cell death. Evaluation of @entity1749 's effects on established orthotopic @entity5 xenografts demonstrated that biweekly intravenous administration of the maximum-tolerated dose of the drug (1 mg/kg) led to significant reductions in the volumes of L3.6pl @entity5 but not Mia-PaCa-2 @entity5 . Laser scanning cytometer-mediated quantification of drug-induced apoptosis in the xenografts confirmed that @entity1749 induced DNA fragmentation and activation of @entity522 in L3.6pl @entity5 but not in Mia-PaCa-2 @entity5 . However, histological examination of drug-treated @entity5 revealed @entity39 and reductions in microvessel density and @entity7 expression in both @entity5 types. Taken together, our results demonstrate that @entity1749 inhibits the growth of @entity1 @entity788 via direct effects on @entity5 cells and indirect effects on the @entity5 vasculature.
