Preclinical study of a Bcl-2 inhibitor in neuroblastoma.
Bibliographic record
Abstract
9563 Background: Neurblastoma (NB) is the most common and deadly extracranial solid tumor of childhood. This malignant tumor exhibits a broad spectrum of clinical features, including spontaneous regression or maturation without any treatment or progression to metastisis leading to death. However, in spite of many therapeutic improvements, only 60% survive long term. In fact, 40% of patients with high-risk NB still relapse and eventually die of the disease despite aggressive combinations of multi-agent chemotherapy. In those cases, new therapeutic strategies must be developed. Studies have shown that BCl-2, a central anti-apoptotic protein, is over-expressed in NB. Although Bcl-2 is not a significant prognostic factor in NB, its increased expression would contribute to chemotherapy resistance. BCl-2 is also shown to be involved in the modulation of autophagy by inhibiting Beclin-1. Therefore, BCl-2 protein represents an attractive target for new therapeutic strategies in NB.The objective of this study is to determine the efficacy in vitro of Obatoclax (OB), a BCl-2 inhibitor, used in monotherapy or in combination to cisplatine (CP), a classical chemotherapeutic agent used in NB treatment, on NB cell survival. Methods: Six NB cell lines (SK-N-DZ, SK-N-FI, SK-N-SH, N91, NB8 and NB10) were treated with OB alone or in association to CP. Cell survival was measured by MTT test. Autophagy was measured by MDC test. Western Blots (WB) were done to evaluate the modulation of apoptotic and autophagic pathways in treated cells. Results: OB used in monotherapy shows promising results on NB cell lines with an average IC50 of 0.12µM. Also, OB demonstrates synergistic effects when associated to CP. The IC50 of CP treated cells varied from 3.183µM to 6.837µM but dropped from 0.003µM to 0.008µM when combined with 0.5µM of OB. Moreover, our WB show an increase in cleaved Caspase-3 and PARP-1 expression, suggesting an upregulation of apoptosis in treated cells. Autophagy is also upregulated confirmed by an increase in autophagic vacuoles and cleaved LC3 II protein. Conclusions: OB used in monotherapy or in combination at potentially therapeutic doses shows promising results in NB. These results will allow for the improvement of NB treatments by introducing a new therapeutic strategy.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".