Alves, CelsoSerrano, EuricoSilva, JoanaRodrigues, CarlosPinteus, SuseteGaspar, HelenaBotana, Luis M.Alpoim, Maria C.Pedrosa, Rui2020-08-282020-08-282020Alves, C., Serrano, E., Silva, J., Rodrigues, C., Pinteus, S., Gaspar, H., Botana, L., Alpoim, M., & Pedrosa, Rui. (2020). Sphaerococcus coronopifolius bromoterpenes as potential cancer stem cell-targeting agents. Biomedicine & Pharmacotherapy. 128. DOI: 10.1016/j.biopha.2020.110275.0753-3322http://hdl.handle.net/10400.8/5112Acknowledgments This work was supported by the Portuguese Foundation for Science and Technology (FCT) through strategic project UID/MAR/04292/ 2020 and UID/Multi/04046/2020 granted to MARE—Marine and Environmental Sciences Centre and BioISI—BioSystems and Integrative Sciences Institute, respectively, through Red2Discovery project (PTDC/ MAR-BIO/6149/2014), co-financed by COMPETE (POCI-01-0145FEDER-016791), through Oncologia de Precisão: Terapias e Tecnologias Inovadoras project (POINT4PAC) (SAICTPAC/0019/2015LISBOA-01-0145-FEDER-016405) and through CROSS-ATLANTIC project (PTDC/BIA-OUT/29250/2017), co-financed by COMPETE (POCI01-0145-FEDER-029250). This work was also funded by the Integrated Programme of SR&TD "Smart Valorization of Endogenous Marine Biological Resources Under a Changing Climate" (reference Centro-010145-FEDER-000018), co-funded by Centro 2020 Programme, Portugal 2020, European Union, through the European Regional Development Fund. FCT is also acknowledged for the grant attributed to J.S. (SFRH/ BD/103255/2014).Cancer is one of the major threats to human health and, due to distinct factors, it is expected that its incidence will increase in the next decades leading to an urgent need of new anticancer drugs development. Ongoing experimental and clinical observations propose that cancer cells with stem-like properties (CSCs) are involved on the development of lung cancer chemoresistance. As tumour growth and metastasis can be controlled by tumourassociated stromal cells, the main goal of this study was to access the antitumor potential of five bromoterpenes isolated from Sphaerococcus coronopifolius red alga to target CSCs originated in a co-culture system of fibroblast and lung malignant cells. Cytotoxicity of compounds (10–500 μM; 72 h) was evaluated on monocultures of several malignant and non-malignant cells lines (HBF, BEAS-2B, RenG2, SC-DRenG2) and the effects estimated by MTT assay. Co-cultures of non-malignant human bronchial fibroblasts (HBF) and malignant human bronchial epithelial cells (RenG2) were implemented and the compounds ability to selectively kill CSCs was evaluated by sphere forming assay. The interleucine-6 (IL-6) levels were also determined as cytokine is crucial for CSCs. Regarding the monocultures results bromosphaerol selectively eliminated the malignant cells. Both 12S-hydroxy-bromosphaerol and 12R-hydroxy-bromosphaerol steroisomers were cytotoxic towards non-malignant bronchial BEAS-2B cell line, IC50 of 4.29 and 4.30 μM respectively. However, none of the steroisomers induced damage in the HBFs. As to the co-cultures, 12R-hydroxy-bromosphaerol revealed the highest cytotoxicity and ability to abrogate the malignant stem cells; however its effects were IL-6 independent. The results presented here are the first evidence of the potential of these bromoterpenes to abrogate CSCs opening new research opportunities. The 12R-hydroxy-bromosphaerol revealed to be the most promising compound to be test in more complex living models.engMarine natural productsRed seaweedLung cancerCancer stem cellsMicroenvironmentInterleukin-6journal article10.1016/j.biopha.2020.110275