Sphaerococcus coronopifolius bromoterpenes as potential cancer stem cell-targeting agents

• Published in: Biomedicine & pharmacotherapy 2020-08, Vol.128, p.110275, Article 110275
• Main Authors: Alves, Celso, Serrano, Eurico, Silva, Joana, Rodrigues, Carlos, Pinteus, Susete, Gaspar, Helena, Botana, Luis M., Alpoim, Maria C., Pedrosa, Rui
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Cancer stem cells; Cell Line, Tumor; Cell Survival - drug effects; Coculture Techniques; Dose-Response Relationship, Drug; Humans; Inhibitory Concentration 50; Interleukin-6; Interleukin-6 - metabolism; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Marine natural products; Microenvironment; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Red seaweed; Rhodophyta - chemistry; Terpenes - isolation & purification; Terpenes - pharmacology; Tumor Microenvironment
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.110275

[Display omitted] •Seaweed derived compounds as cancer stem cells - targeting agents.•Suppression the gap between in vitro and in vivo assays using a co-culture model.•12R-hydroxy-bromosphaerol revealed ability to abrogate the malignant stem cells.•12R-hydroxy-bromosphaerol activity was IL-6 independent. 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 tumour-associated 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.