d,l-Methadone causes leukemic cell apoptosis via an OPRM1-triggered increase in IP3R-mediated ER Ca2+ release and decrease in Ca2+ efflux, elevating [Ca2+]i
Bibliographic record
Abstract
Abstract The search continues for improved therapy for acute lymphoblastic leukemia ( a LL), the most common malignancy in children. Recently, d , l -methadone was put forth as sensitizer for a LL chemotherapy. However, the specific target of d , l -methadone in leukemic cells and the mechanism by which it induces leukemic cell apoptosis remain to be defined. Here, we demonstrate that d , l -methadone induces leukemic cell apoptosis through activation of the mu1 subtype of opioid receptors (OPRM1). d , l -Methadone evokes IP3R-mediated ER Ca 2+ release that is inhibited by OPRM1 loss. In addition, the rate of Ca 2+ extrusion following d , l -methadone treatment is reduced, but is accelerated by loss of OPRM1. These d , l -methadone effects cause a lethal rise in [Ca 2+ ] i that is again inhibited by OPRM1 loss, which then prevents d , l -methadone-induced apoptosis that is associated with activation of calpain-1, truncation of Bid, cytochrome C release, and proteolysis of caspase-3/12. Chelating intracellular Ca 2+ with BAPTA-AM reverses d , l -methadone-induced apoptosis, establishing a link between the rise in [Ca 2+ ] i and d , l -methadone-induced apoptosis. Altogether, our findings point to OPRM1 as a specific target of d , l -methadone in leukemic cells, and that OPRM1 activation by d , l -methadone disrupts IP3R-mediated ER Ca 2+ release and rate of Ca 2+ efflux, causing a rise in [Ca 2+ ] i that upregulates the calpain-1-Bid-cytochrome C-caspase-3/12 apoptotic 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 | 0.002 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".