Abstract 2491: Metformin sensitizes human lung cancer xenografts to ionizing radiation: Response of the AMPK pathway
Bibliographic record
Abstract
Abstract Introduction : Radiation therapy is a standard therapeutic modality in lung cancer (LC). Unfortunately, LC demonstrates radiation resistance and poor response to even high doses of chest radiotherapy. Therefore, there is an urgent need to develop effective and well tolerated radiation sensitizers in LC. Recently, we showed that ionizing radiation (IR) and metformin (MET) activate the energy sensor and tumor suppressor kinase AMP-activated kinase (AMPK). MET enhanced IR activation of AMPK in LC cells and increased the cytotoxicity of IR in clonogenic assays. In the present study we investigated, in human LC xenografts, the radio-sensitizing properties of MET and its effects on the activity of the AMPK pathway in intact tumors. Methods: A549 cells (2×106) were grafted in the franks of Balb/c immunodeficient athymic nude mice and tumors were left to grow to 100 mm3. MET supplementation was delivered in drinking water at a dose of 250 mg/kg daily, and IR of 10 Gy was delivered as a single fraction 7 days after initiation of metformin administration. Eight weeks later animals were euthanized and tumors where isolated. Half of each tumor was snap frozen for preparation of whole tumor lysates and immunoblotting analysis and the other half was fixed and embedded for immunohistochemistry analysis. Tumour growth kinetics and levels of total AMPK, phosphor (P)-AMPK (P-AMPK Thr172) and P-Acetyl-CoA Carboxylase (ACC) and P-Akt were evaluated. Results: MET and IR alone inhibited significantly A549 LC xenograft tumor growth. Furthermore, the combined treatment of MET and IR produce an additive effect and inhibited tumor growth more than each treatment alone. Both IR and MET enhanced AMPK phosphorylation and activity detected by ACC phosphorylation. Similar to tumor growth kinetics, the combined treatment of MET+IR enhanced AMPK activity and phosphorylation above the levels of each treatment alone. However, we also detected that MET and IR treatments also increased significantly the total AMPK α subunit levels in tumor tissues with a consistent potentiation of this effect when the two treatments were combined. On the other hand MET showed a tendency to inhibit basal and radiation-induced Akt phosphorylation levels in xenografts. Our immunoblotting results were verified with immunohistochemistry experiments. Conclusion: Similar to our earlier observations in tissue culture models, the present studies suggest that MET inhibits LC tumour growth and sensitizes them to IR. The two agents mediate both expression and activation of AMPK which appears to be associated with inhibition of Akt. Activation of AMPK by MET and IR in-vivo does not appear to depend on LKB1 as A549 cells are LKB1 null. These results demonstrate the potential of MET to function as a radiation sensitizer in-vivo and support evaluation of this drug in LC clinical trials in combination with radiation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2491. doi:10.1158/1538-7445.AM2011-2491
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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) | 0.003 | 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".