Abstract 4400: Novel combination of carbonic anhydrase inhibitor with a phytochemical for treatment of human bronchial carcinoids
Bibliographic record
Abstract
Abstract Bronchial carcinoids are pulmonary neuroendocrine cell derived tumors comprising typical (TC) and atypical (AT) malignant phenotypes. The 5-year survival rate in metastatic disease, despite multiple current therapies, is 14-25%. Carcinoids are found in the gastrointestinal tract are more frequent (61%) and also more aggressive; however, 31% of carcinoids are located in bronchopumonary system, which can metastize beyond the longs. Therefore, new strategies are needed for effective treatment of carcinoid malignant progression and metastatic disease. The progenitor neuroendocrine cells are O2/CO2 chemosensory. Hypoxia and hypercapnia stimulate secretion of the neuroendocrine associated bioactive amine, serotonin, which can also serve as an autocrine growth factor. CO2 sensing and metabolism is associated with physiological activities of different carbonic anhydrases (CAs) which function in tumor cell pH homeostasis and therein regulation of growth, survival, and metastasis. CAs are abundantly expressed in lung carcinoids. We postulated that acetazolamide (AZ), a pan CA inhibitor, and the anti-tumor phytochemical sulforaphane (SFN), which can inhibit expression of serotonin receptors could function cooperatively and synergistically to inhibit growth of pulmonary carcinoids. A dose dependent effect of AZ (0-80 µM, 48h) and SFN (0-80µM, 48h) on carcinoid cell lines H727 (TC), H835 (intermediate phenotype) and H720 (AT) was assessed in vitro. Both compounds reduced cell viability (via Alamar Blue) and mitochondrial integrity (via JC-1 mitochondrial staining) dose-dependently in all cell lines. IC50 values for cell viability were 9.29 µM (H727), 16.67 µM (H835) and 30.85 µM (H720) for AZ and 51.93 µM (H727), 5.31 µM (H835) and 10.82 µM (H720) for SFN. The mitochondrial integrity JC1 IC50 values were 50.16 µM (H727), 15.52 µM (H835), 11.93 µM (H720) for AZ and 9.29 µM (H727), 16.67 µM (H835) and 30.85 µM (H720) for SFN treatment. Treatment of H727 subcutaneous xenografts in NOD/SCID mice for 2 weeks demonstrated modest growth inhibition with AZ (7%, 20mg/kg) and SFN (23%, 40mg/kg) alone. However, a highly significant reduction (57%; p=0.02) was shown with the combination treatment. Furthermore, the combination did not show any signs of morbidity in treated mice. Since these doses are at the low end and well within clinical range and bioavailability, our results suggest a potential new therapeutic strategy for the treatment of pulmonary carcinoids. The molecular mechanism underlying this synergistic anti-tumor effect, currently under investigation, suggests a novel targeting of tumor cell homeostasis. 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 4400. doi:1538-7445.AM2012-4400
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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) | 0.001 | 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 | 0.001 |
| 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".