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