Sulindac independently modulates extracellular signal-regulated kinase 1/2 and XXXX -dependent protein kinase signaling pathways.

@entity1 @entity5732 @entity5 @entity3963 @entity36326 @entity2733 @entity3546 @entity8262 @entity10521 @entity4675 @entity14 @entity6709 @entity694 @entity204 @entity1366
@entity14 is the second leading cause of @entity5 mortality in the United States. Substantial @entity1 and animal data support the ability of nonsteroidal anti-inflammatory drugs to cause regression of existing @entity694 and prevent new @entity5 formation. The mechanism by which the nonsteroidal anti-inflammatory drug sulindac prevents @entity5 growth is poorly understood and seems complex as sulindac can modulate several growth-related signaling pathways. Sulindac metabolites simultaneously (a) increase cellular @entity8262 and subsequently activate @entity8262 -dependent protein kinase ( @entity6709 ); (b) activate c-jun @entity2733 -terminal kinase ( @entity4675 ); (c) inhibit @entity3963 ( @entity1366 ); and (d) decrease @entity3546 protein expression at times and doses consistent with apoptosis. The purpose of this study was to determine if @entity6709 , @entity1366 , @entity4675 , and @entity3546 are independent targets for sulindac in vitro. Pharmacologic activation of @entity6709 with @entity36326 increases @entity4675 phosphorylation and induces apoptosis in @entity694 cells without modulating @entity1366 phosphorylation or @entity3546 protein expression. Inhibition of @entity1366 with @entity5732 induces apoptosis but fails to activate @entity4675 phosphorylation or down-regulate @entity3546 protein expression. Cotreatment with @entity5732 and @entity36326 synergistically increases apoptosis in @entity14 cells and recapitulates the effects of @entity10521 treatment on @entity1366 , @entity4675 , and @entity3546 . These results indicate that sulindac metabolites modulate @entity1366 and @entity6709 pathways independently in @entity694 cells and suggest that the full apoptotic effect of sulindac is mediated by more than one pathway. Using similar combinatorial approaches in vivo may provide more effective, less toxic chemopreventive and chemotherapeutic strategies. Such therapies could dramatically reduce the incidence and @entity204 rate from @entity14 .
