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Sphaerococcus coronopifolius bromoterpenes as potential cancer stem cell-targeting agents.
Biomedicine & Pharmacotherapy ( IF 7.5 ) Pub Date : 2020-05-30 , DOI: 10.1016/j.biopha.2020.110275
Celso Alves 1 , Eurico Serrano 2 , Joana Silva 1 , Carlos Rodrigues 3 , Susete Pinteus 1 , Helena Gaspar 4 , Luis M Botana 5 , Maria C Alpoim 2 , Rui Pedrosa 1
Affiliation  

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.



中文翻译:

冠状球菌溴虫萜作为潜在的癌症干细胞靶向药物。

癌症是对人类健康的主要威胁之一,由于各种不同的因素,预计其发病率将在未来几十年内增加,从而迫切需要开发新的抗癌药物。正在进行的实验和临床观察表明,具有干样特性(CSCs)的癌细胞参与了肺癌化学耐药性的发展。由于肿瘤生长和转移可通过与肿瘤相关的基质细胞控制,因此本研究的主要目标是获得从冠状球菌中分离的五种溴萜的抗肿瘤潜力靶向CSC的红藻起源于成纤维细胞和肺恶性细胞的共培养系统。在几种恶性和非恶性细胞系(HBF,BEAS-2B,RenG2,SC-DRenG2)的单培养中评估了化合物的细胞毒性(10–500μM; 72小时),并通过MTT分析评估了其作用。实施了非恶性人支气管成纤维细胞(HBF)和恶性人支气管上皮细胞(RenG2)的共培养,并通过球形成分析评估了化合物选择性杀死CSC的能力。还确定了白细胞介素6(IL-6)的水平,因为细胞因子对CSC至关重要。

关于单一培养物的结果,溴三酚选择性地消除了恶性细胞。12 S-羟基-溴菜豆甾醇和12 R-羟基-溴菜豆甾醇异构体均对非恶性支气管BEAS-2B细胞系具有细胞毒性,IC 50分别为4.29和4.30μM。但是,没有一种立体异构体会引起HBF的破坏。对于共培养物,12 R-羟基-溴菜豆酚显示出最高的细胞毒性和消除恶性干细胞的能力。但是它的作用与IL-6无关。

这里介绍的结果是这些溴萜类化合物有潜力消除CSCs开辟新研究机会的潜力的第一个证据。12 R-羟基溴化三苯酚被证明是在更复杂的生活模型中测试的最有希望的化合物。

更新日期:2020-05-30
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