Effect of FK866, NAMPT inhibitor, on small cell lung cancer cell lines.
Bibliographic record
Abstract
e18562 Background: Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme in the primary salvage pathway for nicotinamide adenine dinucleotide (NAD) synthesis. FK866 is a potent and specific small molecule inhibitor of NAMPT. The objective of this study was to validate the effect of NAD depletion on proliferation, and elucidate mechanism of cell death in small cell lung cancer (SCLC) cell lines. Methods: SCLC chemotherapy-sensitive lines (NCI-H209, NCI-H69, NCI-H446, & DMS79) and a resistant cell line (H69AR) were treated with increasing concentrations of FK866. CellTiter-Glo Luminescent Assay was used to measure ATP to assess cell viability, and the lethal dose 50 (LD50) was determined. A non-SCLC cell line (A549) was treated as a comparator. Treated cell lines were assessed for expression of NAMPT, Bcl-2, PARP and caspase-3 cleavage using Western blot. Chemo-sensitization potential by FK866 to doxorubicin and cisplatin was also evaluated. Results: Cell death measured at 72 hours occurred at very low FK866 concentrations (LD50 range = 0.38-7.2 nM) in both chemotherapy-sensitive and -resistant SCLC cell lines compared to the non-SCLC line (LD50= 100 nM). FK866 did not demonstrate synergy with doxorubicin or cisplatin in SCLC. At 24 hours, evidence of increased apoptosis was not observed as measured by Bcl-2 expression and caspase-3 cleavage, suggesting an alternate mechanism of cell death. Further work to establish mechanism is ongoing. Conclusions: This study confirms that SCLC cell lines are very sensitive to NAMPT inhibition by FK866 in vitro. Phase I clinical trials with FK866 suggest this is a well-tolerated drug. FK866 and related compounds may represent a novel treatment approach for SCLC, especially chemotherapy-resistant disease where active agents are desperately needed.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".