Abstract 395: Effect of pantoprazole to enhance activity of docetaxel against human tumor xenografts by inhibiting autophagy
Bibliographic record
Abstract
Abstract Background: Autophagy allows recycling of cellular components and may facilitate cell survival after chemotherapy. Pantoprazole inhibits proton pumps, including that maintaining low pH in endosomes, and is reported to inhibit autophagy (1). Here we evaluate effects of pantoprazole to modify cytotoxicity of the anticancer drug docetaxel, and underlying mechanisms. Methods: Effects of docetaxel+/-pantoprazole were studied against wild-type and autophagy-deficient cultured PC3 cells derived by shRNA, and against four human xenografts. Effects of pantoprazole on autophagy in cultured cells were evaluated by quantifying LC3-I, LC3-II and p62 proteins in Western blots, and by fluorescent microscopy of cells transfected with the tandem sensor RFP-GFP-LC3. Since autophagy is known to be up-regulated in poorly-nourished tumor regions (2), the distribution of drug effects and of autophagy was quantified in tumor sections in relation to blood vessels and hypoxia by immunohistochemistry (IHC) using γH2AX, a marker of DNA damage, cleaved caspase-3, a marker of apoptosis, Ki67, a marker of proliferation and LC3 and p62 to quantify autophagy. Results: Pantoprazole increased toxicity of docetaxel for cultured cells, increased docetaxel-induced expression of γH2AX and cleaved caspase-3 and decreased Ki67 in tumor sections. Pantoprazole increased growth-delay of four human xenografts of low, moderate and high sensitivity to docetaxel, with minimal increase in toxicity. Docetaxel led to increased autophagy throughout tumor sections. Pantoprazole inhibited autophagy, and effects of pantoprazole were reduced against genetically-modified cells with decreased ability to undergo autophagy. Conclusions: Autophagy is a mechanism of resistance to docetaxel chemotherapy that may be modified by pantoprazole to improve therapeutic index. High-dose pantoprazole increases the therapeutic effectiveness of docetaxel in vitro and in vivo, and its main mechanism of action is via inhibition of autophagy. With this rationale, we are undertaking a phase II study of pantoprazole + docetaxel in men with castrate-resistant prostate cancer. References: 1. Udelnow A, Kreyes A, Ellinger S, Landfester K, Walther P, Klapperstueck T, et al. Omeprazole inhibits proliferation and modulates autophagy in pancreatic cancer cells. PLoS One;6(5):e20143. 2. Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther;10(9):1533-41. Citation Format: Qian Tan, Anthony M. Joshua, Jasdeep K. Saggar, Man Yu, Marina Wang, Bradly Wouters, Ian F. Tannock. Effect of pantoprazole to enhance activity of docetaxel against human tumor xenografts by inhibiting autophagy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 395. doi:10.1158/1538-7445.AM2015-395
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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 | 0.000 |
| 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".