Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide
Bibliographic record
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".