Bronchial carcinoids (BC) are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants, the latter being more aggressive. The AC form of BC possesses a higher degree of invasiveness and metastatic potential. It is important to understand how the BC tumor initiating cells (TIC) or cancer stem cells (CSC) in BC account for this phenotype. In order to functionally characterize the suspected BC stem cell fraction, BC cell lines (H727 and H720) were grown under a non-adhesive condition to form 3D spheroids favouring expansion of the TIC. The third generation of spheroids was assessed for clonogenicity, tumorigenicity (xenograft model), stem cell and hypoxia markers, drug resistance, karyotype and microarray analysis compared to parental cells. We previously showed that a pan-carbonic anhydrase inhibitor, acetazolamide (AZ) significantly potentiated the anti-tumor effects of sulforophane (SFN, a natural isothiocyanate with HDACi activity) on these lung carcinoid cell lines in vitro and subcutaneous xenografts. Here we developed an orthotopic lung model to study tumor progression and metastatic behaviour of the spheroid forming BC cells. Orthotopically grown tumors were treated with AZ, SFN and the AZ+SFN combination using previous doses within clinically available ranges. Results demonstrated that the spheroid grown BC cells showed increased clonogenic, tumorigenic, and drug resistance potential, with enhanced expression of stem cell, carbonic anhydrase and hypoxia markers as compared with the control non-spheroid cells, all suggesting selection for the TIC or CSC fraction. As in the subcutaneous model the combination of AZ with SFN was more effective than either single agent alone in inhibiting orthotopic tumor growth and survival. Taken together the evidence indicates that the novel AZ+SFN combination is likely targeting the TIC/CSC population. This offers increased value in terms of the management of BC tumor progression and possible metastasis in BC patients presenting with more aggressive variants.
Citation Format: Narges Baluch, Reza Bayat Mokhtari, Tina Homayouni, Pedram Akbari, Fatemeh Heshmati, Syed S Islam, Sushil Kumar, Karen Aitken, Carrie Fitzpatrick, Herman Yeger. The combination of Acetazolamide and Sulforophane targets the tumor initiating cells in human bronchial carcinoids. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C28.
- ©2015 American Association for Cancer Research.