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Targeting cellular microtubule by phytochemical apocynin exhibits autophagy-mediated apoptosis to inhibit lung carcinoma progression and tumorigenesis.


  • 影响因子:4.09
  • DOI:10.1016/j.phymed.2019.153152
  • 作者列表:"Paul S","Chakrabarty S","Ghosh S","Nag D","Das A","Dastidar DG","Dasgupta M","Dutta N","Kumari M","Pal M","Chakrabarti G
  • 发表时间:2020-02-01

BACKGROUND:Lung cancer is the leading cause of cancer-related deaths worldwide. Several targets have been identified for lung cancer therapy, amongst which 'Microtubule' and its dynamics are the most widely studied and used in therapy. Tubulin-microtubule polymer dynamics are highly sought after targets in the field of anti-cancer drug designing. Natural compounds are important sources for developing anticancer therapeutics owing to their efficacy and lower cytotoxicity. Evidence suggested that therapeutic targeting of microtubule by natural compounds is amongst the most widely used interventions in numerous cancer therapies including lung cancer. PURPOSE:To determine the efficacy of apocynin (a natural compound) in suppressing the progression of lung carcinoma both in vitro and in vivo, along with the identification of targets and the underlying mechanism for developing a novel therapeutic approach. METHODS:We have demonstrated themicrotubule depolymerizing role of apocynin by established protocols in cellular and cell-free system. The efficacy of apocynin to inhibit lung carcinoma progression was studied on A549 cells.The tumoricidal ability of apocynin was studied in BALB/c mice model as well.Mice were classified into 4 groups namely-group II mice as tumor control; group III-IV mice asalso tumor-induced but treated with differential apocynin doses whereas group I mice were kept as normal. RESULTS:Apocynin, showed selective cytotoxicity towards lung cancer cells rather than normal lung fibroblast cells. Apocynin inhibited oncogenic properties including growth, proliferation (p < 0.05), colony formation (p < 0.05), invasion (p < 0.05) and spheroid formation (p < 0.05) in lung cancer cells. Apart from other established properties, apocynin was found to be a novel and potent component to bind with tubulin and depolymerize cellular microtubule network. Apocynin mediated cellular microtubule depolymerization was the driving mechanism to trigger autophagy-mediated apoptotic cell death (p < 0.05) which in turn retarded lung cancer progression. Furthermore, apocynin showed tumoricidal characteristics to inhibit lung tumorigenesis in mice as well. CONCLUSION:Targeting tubulin-microtubule equilibrium with apocynin could be the key regulator to catastrophe cellular catabolic processes to mitigate lung carcinoma. Thus, apocynin could be a potential therapeutic agent for lung cancer treatment.


背景: 肺癌是全球癌症相关死亡的主要原因。已经确定了肺癌治疗的几个靶标,其中 “微管” 及其动力学是最广泛研究和用于治疗的。微管蛋白-微管聚合物动力学在抗癌药物设计领域受到高度关注。天然化合物由于其功效和较低的细胞毒性而成为开发抗癌治疗剂的重要来源。证据表明,天然化合物对微管的治疗性靶向是包括肺癌在内的多种癌症疗法中最广泛使用的干预措施之一。 目的: 研究罗布辛 (一种天然化合物) 在体外和体内对肺癌进展的抑制作用。随着靶标的鉴定和开发新的治疗方法的潜在机制。 方法: 我们已经在细胞和无细胞系统中证实了罗布麻素的微管解聚作用。研究了罗布麻苷对肺癌A549 细胞的抑制作用。在BALB/c小鼠模型上研究了罗布麻苷的杀瘤能力。将小鼠分为 4 组,即-II组小鼠作为肿瘤对照; Iii-iv组小鼠作为肿瘤诱导的但用不同的罗布麻苷剂量处理,而I组小鼠保持正常。 结果: 罗布麻苷对肺癌细胞有选择性杀伤作用,而对正常肺成纤维细胞无选择性杀伤作用。罗布麻素抑制肿瘤生长、增殖 (p < 0.05) 、集落形成 (p < 0.05) 、侵袭 (p < 0.05) 和球体形成 (p <0.05)。在肺癌细胞中。除了其他已确定的性质之外,发现罗布麻蛋白是与微管蛋白结合并解聚细胞微管网络的新的和有效的组分。Apocynin介导的细胞微管解聚是触发自噬介导的凋亡细胞死亡的驱动机制 (p <0.05),从而延缓肺癌的进展。此外,apocynin还显示出抑制小鼠肺肿瘤发生的杀瘤特性。 结论: 以微管蛋白-微管平衡为靶点的罗布麻蛋白可能是突变细胞分解代谢过程减轻肺癌的关键调控因子。因此,罗布麻素可能是肺癌治疗的潜在治疗剂。



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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