Background: The prognosis of patients with metastatic bronchial carcinoid remains poor despite current conventional and targeted therapies. Here we evaluated the therapeutic potential of acetazolamide (AZ; a pan carbonic anhydrase inhibitor affecting pH regulation and homeostasis) and sulforaphane (SFN; a natural isothiocyanate compound targeting multiple pathways in cancer cells), for their anti-cancer properties. Methods: In vitro and in vivo studies were conducted on H-727 (typical carcinoid) and H-720 (atypical carcinoid) bronchial carcinoid cell lines. We developed a lung orthotopic bronchial carcinoid tumor xenograft model in NOD/SCID mice. Results: AZ and/or SFN significantly inhibited cell viability and clonogenic capacity in a dose-dependent manner (0-80 μM, 48 hours and 7 days). AZ and/or SFN downregulated phosphoH3, Ki67, EPCAM, CA9, Akt1 and upregulated p21 and Nrf2 proteins compared to controls as confirmed by Western blot. Upregulation of Nrf2 gene expression was confirmed by qPCR. AZ and/or SFN significantly reduced xenograft growth and serotonin content after two weeks treatment. In the lung orthotopic model, MR imaging at 3 Tesla precisely identified growth of H-727 injected cells in the ipsilateral side, and revealed liver metastasis as confirmed by histology. A tumor initiating cell (TIC) fraction isolated under stem cell culture conditions showing significantly enhanced tumorigenicity was also studied. Conclusions: AZ and/or SFN inhibited tumor survival, proliferation, invasiveness, serotonin secretion and tumorigenic potential of bronchial carcinoid cell lines. Since the combination of AZ+SFN was more effective than either single agent, we postulate that AZ potentiates the effects of SFN by inhibiting PI3K/AKT, which could enhance the inhibitory effect of SFN on P21, Ki67 and phosphoH3. Interestingly, Nrf2 upregulation by both AZ and by SFN suggested a potent antioxidant response. The lung orthotopic tumor model of bronchial carcinoids permits study of carcinoid metastatic progression. As the doses used in this study are clinically bioavailable we suggest that AZ and SFN may have promising potential for carcinoid therapy and resolution of the carcinoid syndrome.
Citation Format: Reza Bayat Mokhtari, Syed S. Islam, Narges Baluch, Karen Aitken, Sushil Kumar, Hai-Ling Margaret Cheng, Mehrdad Yazdanpanah, Khosrow Adeli, Yuanxiang Zhou, Ernest Cutz, Herman Yeger. The anti-tumor effects of acetazolamide and sulforaphane on bronchial carcinoids: Preclinical modeling and mechanism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3133. doi:10.1158/1538-7445.AM2014-3133