CSIG-18. RALOXIFENE SENSITIZES GLIOBLASTOMA CELLS TO HYPOXIA-INDUCED DEATH THROUGH INHIBITION OF RNA STRESS GRANULE DISSOLUTION
Bibliographic record
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumour, and carries a uniformly poor prognosis. Despite aggressive therapy, median survival is only 14 months. Death typically results from treatment failure and local recurrence. The GBM microenvironment is highly hypoxic, and previous work has shown that cells residing in this region are more resistant to treatment. Cytoplasmic RNA stress granules (SGs) form in response to hypoxic stress and act as sites of mRNA triage, allowing translational machinery to focus on the translation of pro-survival mRNA during stress thus increasing the probability of cell survival. We hypothesize that SGs may play a role in hypoxia-induced resistance to therapy. We therefore conducted a drug screen to identify drugs that altered the formation or dissolution of SGs in hypoxia. Utilizing high content array scanning, we screened 1280 currently approved compounds (the Prestwick Drug Library) to identify drugs that inhibited formation or dissolution of SGs. We identified 99 candidate drugs inhibiting SG formation and 129 candidate drugs inhibiting SG dissolution. Our screen identified three selective estrogen receptor modulators (SERMs) as potential novel inhibitors of SG dissolution. The most potent effect was observed with raloxifene, which delays SG dissolution in a dose-dependent manner. When raloxifene was administered to U251 glioma cells prior to hypoxia, the combination achieved synergistic killing of tumour cells. Western blotting for cleaved PARP and LC3II demonstrated increased levels of apoptosis and autophagy, respectively, in combination treatment conditions. Taken together, this data would suggest that raloxifene induces apoptotic and autophagic death in GBM cells through its inhibitory effects on SG dissolution. As raloxifene is a currently approved drug already in use in humans, promising data could lead to a phase III clinical trial in GBM patients.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".