Abstract 2468: Inhibition of autophagy as a potential mechanism by which pantoprazole, a proton pump inhibitor (PPI), enhances the therapeutic effect of docetaxel chemotherapy for solid tumors
Bibliographic record
Abstract
Abstract Purpose: Luciani and colleagues (JNCI 2004; 96:1702-13) have shown that PPIs can increase the effects of chemotherapy, most likely by modifying the acid-base balance across the cell membrane of intracellular organelles such as lysosomes. Lysosomes are required for autophagy, a process important for the survival of cells under certain forms of stress and a possible target for anticancer therapy. Here we evaluated the effect of pantoprazole (PTP) to (i) inhibit autophagy, and (ii) modify the cytotoxic effects of the anticancer drug docetaxel (DOC) in vivo and in vitro. Methods: Autophagy was evaluated by assessing both endogenous LC3B protein and with an optical LC3B fusion reporter (LC3B-GFP-RFP) that enables monitoring of autophagosome formation and fusion with the lysosome. Cytotoxicity of DOC +/−PTP was evaluated by a colony-forming assay for PC3 parental cells, and for cells transfected with shRNAs to inhibit autophagy. Growth delay of three human xenografts was evaluated following multiple doses of DOC+/−PTP. The distribution of drug effects in relation to blood vessels was quantified by γH2AX, and cleaved caspase 3. Results: PTP increased endosomal pH and inhibited autophagy in a dose and time dependent manner. PTP alone was not cytotoxic but increased the cytotoxicity of DOC for PC3 cells, with smaller effects against cells with reduced ability to undergo autophagy. Pre-treatment with PTP increased the growth delay caused by DOC in three different xengografts, with minimal increase in toxicity. Effects of DOC evaluated by γH2AX and by cleaved caspase 3 decreased with increasing distance from tumour blood vessels, but were enhanced by pre-treatment with PTP. Conclusions: PTP increases the therapeutic effectiveness of DOC in vitro and in vivo, and a potential mechanism is inhibition of autophagy. DOC is the preferred chemotherapy for men with metastatic castration-resistant prostate cancer, and we plan a phase II study of PTP + DOC in such patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2468. doi:1538-7445.AM2012-2468
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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) | 0.000 | 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) | 0.005 | 0.001 |
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".