Abstract 5448: The tricyclic anti-depressant amitriptyline inhibits D-cyclin transactivation and induces myeloma cell apoptosis by inhibiting histone deacetylases
Bibliographic record
Abstract
Abstract D-cyclins are universally dysregulated in multiple myeloma and contribute to the pathogenesis and chemoresistance of this disease. To identify novel pharmaceutical inhibitors of cyclin D transactivation, we compiled and screened a library of on-patent and off-patent drugs using NIH 3T3 cells stably expressing the Cyclin D2 promoter-driving a luciferase reporter gene. From this screen we identified the tricyclic antidepressant amitriptyline as a novel inhibitor of Cyclin D2 transactivation. In secondary assays, Amitriptyline reduced expression of cyclins D1, D2, and D3 in myeloma cell lines at low micromolar concentrations across a variety of transforming events including c-maf over-expression (JJN3, KMS11, My5 cells), FGFR3 translocation (KMS11, OPM2 cells), and cyclin D1 translocation (KMS12 cells). Consistent with its effects on D-cyclin expression, amitriptyline arrested cells in the G0/G1 phase of the cell cycle at concentrations associated with its ability to decrease D-cyclins. Decreased cyclin D expression and G1 arrest can induce apoptosis. Therefore we tested the effects of amitriptyline on cell viability. Myeloma cell lines were treated with increasing concentrations of Amit and cell viability was measured by the MTS assay. Amitriptyline reduced the viability of myeloma cells with an IC50 < 20 uM within 72hr. In addition, the combination of amitriptyline and dexamethasone synergistically induced cell death. Cell death and apoptosis were confirmed by Annexin V and PI staining and were associated with activation of Caspase-3 and Poly(ADP-ribose)Polymerase (PARP) as detected by immunoblotting. To understand the mechanism by which amitryptiline inhibits D-cyclin transactivation and induces cell death, we examined the effects of this compound on HDAC levels and activity. By immunoblotting, treatment with amitriptyline increased levels of acetyl-Histone 3 in myeloma cell lines. Furthermore amitriptyline decreased levels of HDACs 3, 6, 7 and 8 in examined cell lines with a concentration consistent with the cell death and cyclin D2 inhibition. Thus, in summary, amitriptyline inhibits D-cyclin transactivation in myeloma cells that is associated with reductions in HDAC levels. Given the preclinical activity of amitriptyline in myeloma, this work highlights a potential therapeutic strategy for this disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5448.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 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) | 0.004 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".