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Fullerene Derivatives as Lung Cancer Cell Inhibitors: Investigation of Potential Descriptors Using QSAR Approaches.

富勒烯衍生物作为肺癌细胞抑制剂: 使用QSAR方法研究潜在描述符。

  • 影响因子:4.76
  • DOI:10.2147/IJN.S243463
  • 作者列表:"Huang HJ","Kraevaya OA","Voronov II","Troshin PA","Hsu SH
  • 发表时间:2020-04-14

Background:Nanotechnology-based strategies in the treatment of cancer have potential advantages because of the favorable delivery of nanoparticles into tumors through porous vasculature. Materials and Methods:In the current study, we synthesized a series of water-soluble fullerene derivatives and observed their anti-tumor effects on human lung carcinoma A549 cell lines. The quantitative structure-activity relationship (QSAR) modeling was employed to investigate the relationship between anticancer effects and descriptors relevant to peculiarities of molecular structures of fullerene derivatives. Results:In the QSAR regression model, the evaluation results revealed that the determination coefficient r2 and leave-one-out cross-validation q2 for the recommended QSAR model were 0.9966 and 0.9246, respectively, indicating the reliability of the results. The molecular modeling showed that the lack of chlorine atom and a lower number of aliphatic single bonds in saturated hydrocarbon chains may be positively correlated with the lung cancer cytotoxicity of fullerene derivatives. Synthesized water-soluble fullerene derivatives have potential functional groups to inhibit the proliferation of lung cancer cells. Conclusion:The guidelines obtained from the QSAR model might strongly facilitate the rational design of potential fullerene-based drug candidates for lung cancer therapy in the future.


背景: 基于纳米技术的癌症治疗策略具有潜在的优势,因为纳米颗粒通过多孔脉管系统有利地递送到肿瘤中。 材料和方法: 在本研究中,我们合成了一系列水溶性富勒烯衍生物,并观察了它们对人肺癌A549 细胞株的抗肿瘤作用。采用定量构效关系 (QSAR) 模型研究了富勒烯衍生物的抗癌作用与分子结构特性相关的描述符之间的关系。 结果: 在QSAR回归模型中,评价结果显示推荐QSAR模型的决定系数r2 和留一交叉验证q2 分别为 0.9966 和 0.9246,表明结果的可靠性。分子模拟表明,饱和烃链中缺少氯原子和较低数量的脂肪族单键可能与富勒烯衍生物的肺癌细胞毒性呈正相关。合成的水溶性富勒烯衍生物具有抑制肺癌细胞增殖的潜在官能团。 结论: 从QSAR模型中获得的指南可能有力地促进未来潜在的基于富勒烯的肺癌治疗候选药物的合理设计。



作者列表:["Mammana M","Zuin A","Serra E","Bellini A","Rea F"]

METHODS::Pulmonary artery sling is a rare congenital anomaly of the origin and course of the left pulmonary artery. Patients with this condition typically present with respiratory failure in young infancy, and asymptomatic cases are uncommon. We describe the case of an adult patient with a lung adenocarcinoma of the right upper lobe, extending into the hilum and superior mediastinum, and with a previously unknown pulmonary artery sling anomaly. The local invasiveness of the tumor and the peculiar vascular anatomy contributed to a unique surgical scenario, wherein multiple reconstructive procedures were required.

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作者列表:["Hata A","Nakajima T","Matsusaka K","Fukuyo M","Morimoto J","Yamamoto T","Sakairi Y","Rahmutulla B","Ota S","Wada H","Suzuki H","Matsubara H","Yoshino I","Kaneda A"]

METHODS::Patients with idiopathic pulmonary fibrosis (IPF) have higher risk of developing lung cancer, for example, squamous cell carcinoma (SCC), and show poor prognosis, while the molecular basis has not been fully investigated. Here we conducted DNA methylome analysis of lung SCC using 20 SCC samples with/without IPF, and noncancerous lung tissue samples from smokers/nonsmokers, using Infinium HumanMethylation 450K array. SCC was clustered into low- and high-methylation epigenotypes by hierarchical clustering analysis. Genes hypermethylated in SCC significantly included genes targeted by polycomb repressive complex in embryonic stem cells, and genes associated with Gene Ontology terms, for example, "transcription" and "cell adhesion," while genes hypermethylated specifically in high-methylation subgroup significantly included genes associated with "negative regulation of growth." Low-methylation subgroup significantly correlated with IPF (78%, vs. 17% in high-methylation subgroup, p = 0.04), and the correlation was validated by additional Infinium analysis of SCC samples (n = 44 in total), and data from The Cancer Genome Atlas (n = 390). The correlation between low-methylation subgroup and IPF was further validated by quantitative methylation analysis of marker genes commonly hypermethylated in SCC (HOXA2, HOXA9 and PCDHGB6), and markers specifically hypermethylated in high-methylation subgroup (DLEC1, CFTR, MT1M, CRIP3 and ALDH7A1) in 77 SCC cases using pyrosequencing (p = 0.003). Furthermore, low-methylation epigenotype significantly correlated with poorer prognosis among all SCC patients, or among patients without IPF. Multivariate analysis showed that low-methylation epigenotype is an independent predictor of poor prognosis. These may suggest that lung SCC could be stratified into molecular subtypes with distinct prognosis, and low-methylation lung SCC that significantly correlates with IPF shows unfavorable outcome.

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作者列表:["Zhang L","Yang Y","Chai L","Bu H","Yang Y","Huang H","Ran J","Zhu Y","Li L","Chen F","Li W"]

METHODS::The role of Fyn-related kinase (FRK) in malignant tumors remains controversial. Our study investigated the function of FRK in lung cancer. Immunohistochemistry staining and generating a knockout of FRK by CRISPR/Cas9 in H1299 (FRK-KO-H1299) cells were strategies used to explore the role of FRK. Immunohistochemistry staining indicated that FRK expression was elevated in 223 lung cancer tissues compared to 26 distant normal lung tissues. FRK contributed to poor survival status in lung cancer patients and acted as a predictor for poor prognosis of lung cancer. Knockout of FRK by CRISPR/Cas9 markedly inhibited proliferation, invasion, colony formation and epithelial-mesenchymal transition (EMT) process in the lung cancer cell line H1299. Further exploration indicated that FRK-KO damaged the stemness phenotype of H1299 by inhibiting CD44 and CD133 expression. Seahorse detection and a U-13 C flux assay revealed that FRK-KO induced metabolism reprogramming by inhibiting the Warburg effect and changing the energy type in H1299 cells. Epidermal growth factor stimulation recovered the expression of FRK and biological functions, metabolic reprogramming and stemness phenotype of H1299 cells. FRK plays an oncogenic role in lung cancer cells via a novel regulation mechanism of enhancing the stemness of H1299 cells by inducing metabolism reprogramming, which finally promotes EMT and metastasis. Our study also indicates that FRK could be used as a potential therapeutic target for drug development.

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