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Antihelminthic Niclosamide Induces Autophagy and Delayed Apoptosis in Human Non-small Lung Cancer Cells In Vitro and In Vivo.

抗蠕虫氯硝柳胺在体内外诱导人非小细胞肺癌细胞自噬和延迟凋亡。

  • 影响因子:0
  • DOI:10.21873/anticanres.14082
  • 作者列表:"Chai WH","Li YR","Lin SH","Chao YH","Chen CH","Chan PC","Lin CH
  • 发表时间:2020-03-01
Abstract

BACKGROUND/AIM:Niclosamide is an antihe-minthic drug that has shown cytotoxic effects on non-small cell lung carcinoma (NSCLC) cells. However, the exact mechanisms underlying the anti-tumour activity of niclosamide in NSCLC cancer cells remains to be defined. The aim of this study was to evaluate the antitumor activity of niclosamide in human A549 and CL1-5 non-small cell lung cancer cells using in vitro and in vivo. MATERIALS AND METHODS:We investigated the effects of niclosamide on cell viability, apoptosis, the mitochondrial membrane potential (MMP; Δϕm), and autophagy and apoptosis-related protein expression in human A549 and CL1-5 non-small cell lung cancer cells. RESULTS:Niclosamide induced mainly caspase-independent apoptosis through apoptosis-inducible factor (AIF) translocation to the nucleus upon mitochondria damage. Moreover, niclosamide-induced autophagy may act as adaptive response against apoptosis. AMPK/AKT/mTOR pathway were involved in niclosamide-induced cell death and autophagy in response to ATP depletion. Furthermore, niclosamide efficiently suppressed tumor growth and induce autophagy in vivo. CONCLUSION:Niclosamide induced apoptosis by activating the intrinsic and caspase-independent pathway in human A549 and CL1-5 non-small cell lung cancer cells. Therefore, niclosamide is a potential candidate for anti-NSCLC therapy.

摘要

背景/目的: 氯硝柳胺是一种抗癌症药物,对非小细胞肺癌 (NSCLC) 细胞显示出细胞毒性作用。然而,氯硝柳胺在NSCLC癌细胞中抗肿瘤活性的确切机制仍有待确定。本研究的目的是在体外和体内评价氯硝柳胺对人A549 和CL1-5 非小细胞肺癌细胞的抗肿瘤活性。 材料和方法: 我们研究了氯硝柳胺对细胞活力,细胞凋亡,线粒体膜电位 (MMP; Δ ϕm),和自噬及凋亡相关蛋白在人A549 和CL1-5 非小细胞肺癌细胞中的表达。 结果: 氯硝柳胺主要通过凋亡诱导因子 (AIF) 在线粒体损伤时易位至细胞核而诱导caspase非依赖性细胞凋亡。此外,氯硝柳胺诱导的自噬可作为抗凋亡的适应性反应。AMPK/AKT/mTOR通路参与了氯硝柳胺诱导的细胞死亡和响应ATP耗竭的自噬。此外,氯硝柳胺在体内有效抑制肿瘤生长并诱导自噬。 结论: 氯硝柳胺通过激活人A549 和CL1-5 非小细胞肺癌细胞内源性和非半胱天冬酶依赖性途径诱导细胞凋亡。因此,氯硝柳胺是抗NSCLC治疗的潜在候选药物。

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影响因子:6.93
发表时间:2020-01-15
DOI:10.1002/ijc.32532
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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影响因子:6.93
发表时间:2020-01-01
DOI:10.1002/ijc.32530
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"]

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肺肿瘤方向

肺肿瘤,又叫支气管肺癌,是常见的恶性肿瘤之一。肺肿瘤的治疗为包括手术、中药、放疗、化疗及免疫等多学科的综合治疗。

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