Abstract 314: Low-dose NAMPT inhibition by FK866 initiates autophagy to counteract cellular energy crisis, which is overridden by apoptosis at higher drug concentrations
Bibliographic record
Abstract
Abstract Chronic lymphocytic leukemia (CLL) is characterized by accumulation of mature, but immune-incompetent monoclonal B-lymphocytes. Dependent on external stimuli, these CLL-cells can either be quiescent or active, with the latter being suggested to be critical for disease aggressiveness, drug-resistance and relapse. The active state of the malignant cells is associated with abnormal cellular metabolism. Nicotinamide adenine dinucleotide (NAD) is a critical factor in cellular metabolism by acting as coenzyme in ATP-synthesizing mitochondrial electron transport chain reactions. Nicotinamide phoysphorybosyltransferase NAMPT is the rate-limiting enzyme for nicotinamide-salvaging to NAD. NAMPT has been demonstrated to be over-expressed in several cancer entities. Also in CLL-cells increased NAMPT expression was found in tissue-associated CLL-cells by gene expression profiling. FK866 is a NAMPT-inhibitor and has been demonstrated to selectively reduce cancer cell viability mainly in solid tumors. FK866 has also been demonstrated to be effective in several hematological cell lines where it leads to ATP-reduction and delayed induction of cell death. While some studies proposed apoptosis-induction, others showed caspase-independent autophagic cell death. Most available data about the antitumor effect of FK866 is derived from studies in cell lines. Further, inconsistencies about sensitivity of different cell lines to FK866 in the literature strongly warrant studies in primary cells. In this study we address the impact of FK866-mediated NAMPT-inhibition on cellular energy content, cell viability and involvement of apoptotic and autophagic signaling in primary CLL-cells. FK866 potently reduced cellular NAD-content at low concentration of 10 nM as early as day one. This was followed by reduction in cellular ATP-content at day two and subsequent viability reduction at day three as assessed by flow cytometric measure of annexin V/PI staining. FK866 at 1 nM reduced cellular NAD-content slightly at day one with no significant further downregulation up to day four. At this drug concentration we neither saw significant ATP-downregulation, nor viability reduction up to day four. In contrast, at 1 nM FK866 we saw protection from spontaneous apoptosis by flow cytometry, stabilization of caspases 9 and 3, upregulation of antiapoptotic proteins XIAP and Mcl1 going along with increased phosphorylation of mTOR and AMPK. We conclude that downregulation of NAD by FK866 results in a cellular energy crisis, which CLL-cells counteract by initial induction of autophagy. At low FK866 concentrations this autophagic response is sufficient to compensate for energy loss and to prevent further downstream death signaling, while at higher concentration apoptosis overrides autophagy. Citation Format: Eric Bouchard, Iris Gehrke, Versha Banerji. Low-dose NAMPT inhibition by FK866 initiates autophagy to counteract cellular energy crisis, which is overridden by apoptosis at higher drug concentrations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 314. doi:10.1158/1538-7445.AM2014-314
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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) | 0.005 | 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".