Inhibition of phosphatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells.
Bibliographic record
Abstract
Human pancreatic adenocarcinoma cell lines PK1 and PK8 are resistant to the clinically relevant chemotherapy agent gemcitabine. Cell cycle analysis demonstrated an accumulation of cells in the early S phase during treatment with 20 microM gemcitabine, consistent with its mode of action as a DNA chain terminator. However, apoptosis was evident in only a small percentage of cells. Similar to pancreatic cancers in the clinic, PK1 and PK8 cells carry constitutively active Ki-Ras and overexpress multiple receptor tyrosine kinases. Both genetic abnormalities may potentially up-regulate the activity of the phosphatidylinositide 3-kinase (P13K)-protein kinase B (PKB)/Akt cell survival pathway. The current study examined the relevance of this pathway in the modulation of drug resistance in PK1 and PK8 cells. After exposure to 20 microM gemcitabine for 48 h and in the continuous presence of the drug, treatment with the P13K inhibitors wortmannin (50-200 nM) and LY294002 (15-120 microM) for 4 h substantially enhanced apoptosis in a concentration-dependent manner as compared with treatment with gemcitabine alone, as determined by the loss of mitochondrial membrane potential and the increase in propidium iodide uptake using flow cytometry. Furthermore, Western blotting showed that the reduction of phosphorylated PKB/Akt levels correlated with the enhancement of gemcitabine-induced apoptosis, suggesting that the PI3K-PKB/Akt pathway plays a significant role in mediating drug resistance in human pancreatic cancer cells. PI3K inhibitors may have therapeutic potential when combined with gemcitabine in the treatment of pancreatic cancers.
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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) | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".