Clusterin knockdown using the antisense oligonucleotide OGX‐011 re‐sensitizes docetaxel‐refractory prostate cancer PC‐3 cells to chemotherapy
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Bibliographic record
Abstract
OBJECTIVES: To characterize changes in secretory clusterin (sCLU) expression in prostate cancer cells after treatment with docetaxel and to determine whether sCLU knockdown can re-introduce chemosensitivity in a docetaxel-resistant, androgen-independent human prostate cancer model. PATIENTS AND METHODS: A tissue microarray was constructed for 84 radical prostatectomy (RP) specimens from a multicentre Phase II trial of neoadjuvant combined androgen ablation and docetaxel (CUOG-P01a) and assessed for changes in the expression of the cytoprotective chaperone sCLU. The human prostate cancer cell line PC-3 was repeatedly exposed to docetaxel chemotherapy in vitro, and a docetaxel-resistant cell subline (PC-3dR) was developed and analysed. RESULTS: sCLU levels were significantly higher in RP specimens treated with neoadjuvant combined androgen ablation and docetaxel than in untreated specimens. Similarly, sCLU expression increased 2.5-fold in the newly developed docetaxel-refractory PC-3dR cell line compared with parental PC-3 cells. There was a dose-dependent and sequence-specific decrease in sCLU levels in PC-3dR cells using OGX-011, an antisense oligonucleotide against human sCLU. OGX-011 and small-interference RNA both chemosensitized PC-3dR cells to docetaxel and mitoxantrone in vitro and apoptotic rates in PC-3dR cells were significantly increased when OGX-011 was combined with docetaxel. In vivo, growth of PC-3dR xenografts in nude mice was synergistically inhibited by OGX-011 combined with paclitaxel or mitoxantrone (by 76% and 44% compared with their mismatch controls, respectively). CONCLUSION: The present findings indicate that targeted knockdown of sCLU enhances the effects of cytotoxic chemotherapy in docetaxel-refractory cells, and provide preclinical proof of principle for clinical trials testing OGX-011 in second-line chemotherapy regimens for patients with docetaxel-refractory prostate cancer.
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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) | 0.000 | 0.000 |
| 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 | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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 it