Abstract 4538: Inhibition of mitochondrial protein synthesis with antimicrobial tigecycline preferentially induces cell death in leukemia cells
Bibliographic record
Abstract
Abstract To identify known drugs with unrecognized anti-leukemia activity, we compiled a library of 500 on patent and off patent compounds, and screened it to identify compounds cytotoxic to leukemia cell lines. From this screen we identified Tigecycline, an antibiotic approved for the treatment of cutaneous and intra-abdominal infections. Tigecycline induced cell death in leukemia cell lines (LD50 3 to 8 μM, n = 6 cell lines) and primary Acute Myeloid Leukemia (AML) patient samples (LD50 5-10 μM, n = 7), preferentially over normal hematopoietic cells (10% cell death at 20 μM, n = 4) by MTS assays and Annexin V staining. Likewise, in colony formation assays, Tigecycline (5μM) reduced the clonogenic growth of primary AML patient samples (n = 4) by 95±1.5 %, demonstrating an effect on leukemia progenitor cells. In contrast, 5 μM of Tigecycline reduced the clonogenic growth of normal hematopoetic cells by 34± 5% (n = 5). Although Tigecycline is structurally related to tetracycline and minocycline, these drugs were not cytotoxic towards AML cell lines up to 25 μM. Thus, Tigecycline appears preferentially cytotoxic to leukemia cells at pharmacologically achievable concentrations. Given the anti-leukemic effects of Tigecycline in vitro, we evaluated the efficacy of Tigecycline as a potential anti-leukemic agent in vivo. Mice injected subcutaneously with OCI-AML2 leukemia cells were treated with Tigecycline 50 mg/kg i.p. daily. Compared to control, Tigecycline decreased tumour mass and volume without toxicity. We also assessed the effect of Tigecycline on primary AML stem cells defined by their ability to initiate leukemic engraftment in vivo. NOD-SCID mice were injected intra-femorally with primary AML cells. Two weeks after injection, mice were treated with Tigecycline 50 mg/kg i.p. daily for two weeks. After treatment, engraftment of human AML cells was measured by flow cytometry. Compared to control, Tigecycline decreased engraftment of AML cells without toxicity. Tigecycline binds and inhibits the bacterial 30S ribosome. Bacterial ribosomes are more homologous to mitochondrial ribosomes than cytosolic ribosomes, so we compared the effects of Tigecycline on mitochondrial and cytosolic protein synthesis. At times preceding the onset of cell death, Tigecycline decreased levels of the mitochondrial protein Cox-1. In contrast, it did not decrease the expression of cytosolic short half-life proteins Bcl-XL and XIAP, suggesting a preferential effect on mitochondrial protein synthesis. Thus, Tigecycline demonstrated preclinical activity through a mechanism related to mitochondrial protein synthesis inhibition. Moreover, Tigecycline appeared cytotoxic to leukemia stem cells over normal hematopoetic stem cells. Given its prior pharmacology and toxicology testing, Tigecycline could be rapidly repositioned for a new anti-leukemic indication. 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 4538.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| 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) | 0.005 | 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".