Caspase-3, a novel therapeutic approach to the treatment of multiple myeloma
Bibliographic record
Abstract
The karyotypically silent t(4;14)(p16;q2.3) translocation occurs in approximately 15% of all multiple myeloma (MM) cases, and results in the ectopic expression of fibroblast growth factor receptor 3 (FGFR3). In previous work we overexpressed FGFR3 or the constitutively active FGFR3-TD mutant in an interleukin-6 (IL-6)-dependent murine myeloma cell line, B9. High expression levels of FGFR3 conferred IL-6 independence, increased phosphorylation of STAT3 and upregulated the anti-apoptotic factor bcl-xL. Since bcl-xL can confer chemo-resistance in cancer cells, we hypothesized that FGFR3 overexpression may be sufficient to confer drug resistance to malignant plasma cells. To examine this issue, we tested FGFR3 expressing B9 cells for chemotherapy sensitivity. Melphalan or Doxorubicin both resulted in cell death comparable to controls at low concentrations of drug. In contrast no cell death was observed following exposure of FGFR3 engineered cell lines to Dexamethasone. Believing that this observed Dexamethasone resistance was due to the upregulation of bcl-xL, a bcl-x L antisense oligonucleotide was employed. Upon treatment with this oligonucleotide, FGFR3 expressing B9 cells were rendered sensitive to Dexamethasone. Activated caspase-3 cleaves proteins essential for cell survival, including bcl-x L. To explore the potential of caspase-3 as a cytotoxic molecule in the treatment of MM, the murine myeloma cell line, B9BM1, was transduced with an RU486-inducible caspase-3 retrovirus (B9BM-C3). After induction with RU486, apoptotic cell death of B9BM-C3 cells began by 4 hours and was complete by 48 hours post-induction, while non-transduced cells remained viable. Annexin V staining demonstrated 40%, 78% and 97% apoptotic cell death at 18, 24 and 30 hours post-induction. In co-culture experiments, induced B9BM-C3 cells generated a significant bystander effect. By MTT assay, a mix of 20:80 (B9BM-C3:parental cells) resulted in the death of 80% of the unmodified parental controls. B9BM-C3 cells formed tumors after subcutaneous injection in mice. Early treatment of these mice with RU486 eradicated tumor. Inducing caspase-3 expression in myeloma cells rapidly results in cell death and provides collateral cell damage via a putative bystander effect. These results indicate that therapeutic attempts to induce caspase-3 in myeloma cells may prove useful in the treatment of MM.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".