title: Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide.
abstract: Non-steroidal anti-inflammatory drugs such as sulindac inhibit human colorectal carcinogenesis through a mechanism involving the direct inhibition of cyclooxygenase (Cox)-2. However, a wealth of recent evidence indicates that these agents might elicit their effects through mechanisms independently of Cox-2. In this study, we investigated the effects of sulindac and its metabolite, sulindac sulfide on modulation of the critical survival kinase, protein kinase B (PKB). Here, we demonstrate for the first time that treatment with either sulindac or sulindac sulfide results in a decrease in PKB activity, and we provide compelling evidence that this occurs through two distinct mechanisms. Additionally, we report that overexpression of, and conditional activation of PKB attenuates the apoptotic effects of sulindac, but not for sulindac sulfide - the metabolic metabolite of sulindac. We also demonstrate that treatment with sulindac sulfide, but not sulindac, results in a very early robust activation of both caspase-8 and -9. Furthermore, we show that the apoptotic effects of sulindac sulfide can be reverted by both the caspase-8 and -9 inhibitors. Evidence is provided to indicate that PKB is targeted by robust caspase activation due to sulindac sulfide. Hence, further investigation into the mechanisms regulating conversion of sulindac to sulindac sulfide (or direct use of the latter compound), may enhance our ability to target cancers with enhanced signaling through the growth factor-->phosphatidylinositol 3-kinase pathway.
authors: Department of Medicine, University of British Columbia, Jack Bell Research Center, Vancouver, BC V6H 3Z6, Canada.
authors: Anthony
authors: A
authors: Marotta
authors: Kuljit
authors: K
authors: Parhar
authors: Rajinder
authors: R
authors: Hundal
authors: Vincent
authors: V
authors: Duronio
authors: Baljinder
authors: B
authors: Salh