Hypoxia prevents etoposide-induced DNA damage in cancer cells through a mechanism involving hypoxia-inducible factor 1
Bibliographic record
Abstract
Intratumoral hypoxia is associated with resistance to therapy in many human cancers, and preexposure of tumor cells to hypoxia confers multidrug resistance. Whereas most anticancer drugs kill proliferating tumor cells by causing DNA damage, a role for hypoxia in the prevention and/or repair of drug-induced DNA damage has not been clear. Using the alkaline comet assay, we provide direct evidence that hypoxia-induced resistance to etoposide in human tumor cells (MDA-MB-231 breast carcinoma and DU-145 prostatic adenocarcinoma) is mainly due to prevention of drug-induced DNA damage (i.e., strand breaks) and that the amount of DNA damage present immediately after etoposide exposure is a good independent predictor of clonogenic survival. Our results also revealed that preexposure to hypoxia did not affect the apparent DNA repair capacity of cells. These findings indicate that the extent of DNA damage resulting from etoposide exposure is a more important determinant of survival than subsequent events after DNA damage. Furthermore, immunofluorescence analysis showed that, in a subpopulation of cells, preexposure to hypoxia decreased the levels of topoisomerase IIalpha, an enzyme that generates DNA strand breaks when poisoned with etoposide. Treatment of cells with small interfering RNA targeting hypoxia-inducible factor 1 prevented the hypoxia-induced decreases in topoisomerase IIalpha levels, abolished the protective effect of hypoxia against etoposide-induced DNA damage, and inhibited hypoxia-induced etoposide resistance. These findings support a model of hypoxia-induced drug resistance in which etoposide-induced DNA damage is prevented by HIF-1-dependent adaptations to hypoxia.
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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".