Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide

Abstract

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.

Synergistic cytotoxic effect of sulindac and pyrrolidine dithiocarbamate against ovarian cancer cells

“…4). Increased level of Bcl-2 and decreased expression of procaspase-9 (reciprocally proportional to the active form of caspase-9) argues for the mitochondrial apoptotic pathway and is in agreement with results of other investigators showing correlation of caspase-9 activation and cancer cell death following incubation with sulindac or sulindac sulfide (16) or PDTC (26). In our model, susceptibility of OVA-14 cells to the cytotoxic effect of sulindac and PDTC was not related to the expression of COX-1/COX-2 since both sulindac sulfide (an active inhibitor of cyclooxygenases in vitro ) and sulindac (inactive compound) synergized with PDTC.…”