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BMC Cancer
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Carcinoid Tumor | Research article

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane

Authors: Reza Bayat Mokhtari, Narges Baluch, Evgeniya Morgatskaya, Sushil Kumar, Angelo Sparaneo, Lucia Anna Muscarella, Sheyun Zhao, Hai-Ling Cheng, Bikul Das, Herman Yeger

Published in: BMC Cancer | Issue 1/2019

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Abstract

Background

Bronchial carcinoids are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants, the latter being more aggressive, invasive and metastatic. Studies of tumor initiating cell (TIC) biology in bronchial carcinoids has been hindered by the lack of appropriate in-vitro and xenograft models representing the bronchial carcinoid phenotype and behavior.

Methods

Bronchial carcinoid cell lines (H727, TC and H720, AC) were cultured in serum-free growth factor supplemented medium to form 3D spheroids and serially passaged up to the 3rd generation permitting expansion of the TIC population as verified by expression of stemness markers, clonogenicity in-vitro and tumorigenicity in both subcutaneous and orthotopic (lung) models. Acetazolamide (AZ), sulforaphane (SFN) and the AZ + SFN combination were evaluated for targeting TIC in bronchial carcinoids.

Results

Data demonstrate that bronchial carcinoid cell line 3rd generation spheroid cells show increased drug resistance, clonogenicity, and tumorigenic potential compared with the parental cells, suggesting selection and expansion of a TIC fraction. Gene expression and immunolabeling studies demonstrated that the TIC expressed stemness factors Oct-4, Sox-2 and Nanog. In a lung orthotopic model bronchial carcinoid, cell line derived spheroids, and patient tumor derived 3rd generation spheroids when supported by a stroma, showed robust tumor formation. SFN and especially the AZ + SFN combination were effective in inhibiting tumor cell growth, spheroid formation and in reducing tumor formation in immunocompromised mice.

Conclusions

Human bronchial carcinoid tumor cells serially passaged as spheroids contain a higher fraction of TIC exhibiting a stemness phenotype. This TIC population can be effectively targeted by the combination of AZ + SFN. Our work portends clinical relevance and supports the therapeutic use of the novel AZ+ SFN combination that may target the TIC population of bronchial carcinoids.
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Metadata
Title
Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane
Authors
Reza Bayat Mokhtari
Narges Baluch
Evgeniya Morgatskaya
Sushil Kumar
Angelo Sparaneo
Lucia Anna Muscarella
Sheyun Zhao
Hai-Ling Cheng
Bikul Das
Herman Yeger
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-6018-1

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