天然化合物imperialine新型抗肿瘤功能治疗非小细胞肺癌的机理和治疗研究。,Journal of Ethnopharmacology

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天然化合物imperialine新型抗肿瘤功能治疗非小细胞肺癌的机理和治疗研究。
Journal of Ethnopharmacology ( IF 4.8 ) Pub Date : 2019-10-13 , DOI: 10.1016/j.jep.2019.112283
Qing Lin ₁ , Mengke Qu ₂ , Hirak K Patra ₃ , Shanshan He ₂ , Luyao Wang ₂ , Xun Hu ₄ , Linyu Xiao ₂ , Yu Fu ₂ , Tao Gong ₂ , Qin He ₂ , Ling Zhang ₂ , Xun Sun ₂ , Zhirong Zhang ₂

Affiliation

Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Pharmaceutics, College of Polymer Science and Engineering, West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China; Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, CB3 0AS, United Kingdom.
Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Pharmaceutics, College of Polymer Science and Engineering, West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China.
Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, CB3 0AS, United Kingdom; Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, 58185, Sweden; Wolfson College, University of Cambridge, Cambridge, CB3 9BB, United Kingdom.
Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Pharmaceutics, College of Polymer Science and Engineering, West China School of Pharmacy, Sichuan University, Chengdu, 610041, PR China; CQ MEDVT CO., LTD, Chongqing, 401122, PR China.

人种药理学关系牛肝贝母（BFC）是一种中药，长期以来一直作为支气管肺病的草药处方中不可或缺的成分，因为它具有公认的强抗炎作用和肺部协调作用。有趣的是，很少有传统中医的病例报道，他们发现它有助于抗肿瘤治疗。金枪鱼碱是从BFC中提取的最受青睐的活性物质之一，已被广泛认为是一种抗炎剂。研究的目的本研究的目的是提供体内和体外的第一手证据，以证明imperialine对非小细胞肺癌（NSCLC）具有抗癌作用，并探讨其分子机制。抗肿瘤活性。也有必要检查其全身毒性，并研究如何制定可行的方法来进行帝国主义的临床翻译。材料与方法使用体内和体外方法研究抗衡的苦参碱非NSCLC功效，其中选择A549细胞系作为体外模型NSCLC细胞，并构建了A549荷瘤小鼠模型用于体内研究。通过一系列主要的分子生物学方法，包括免疫组织化学，蛋白质印迹和酶联免疫吸附试验，首次系统地探索了详细的潜在抗癌机制。使用健康的裸鼠，通过检查血流图和组织病理学评估了imperialine治疗的毒性。使用薄膜水合作用方法开发了一种加载有抗老药的脂质体药物递送系统，以评估靶标特异性递送。结果结果表明，imperialine可以通过炎症-癌症反馈回路抑制NSCLC肿瘤和相关炎症，在该回路中，imperialine可以显着抑制NF-κB的活性。靶向NSCLC的脂质体系统已成功开发，可用于靶向药物递送。开发的平台可以有利地增强帝国细胞的摄取和体内肿瘤部位的积累，从而提高总体抗肿瘤效果。毒性试验表明，非苦参碱治疗不会显着干扰小鼠的血细胞计数或对主要器官造成任何重大损害。结论Imperialine可在体内外对NSCLC发挥抗癌作用，并且这种先前未知的功能与以NF-κB为中心的炎症-癌症反馈回路有关。Imperialine介导的抗癌活性不是通过细胞毒性，而是表现出强大的全身安全性。此外，我们开始的基于脂质体的系统将极大地增强imperialine的治疗效果，同时在细胞模型和NSCLC模型中均表现出极低的副作用。这项工作已将Imperialine确定为一种有前途的新型抗癌化合物，并提供了一种有效的靶标传递解决方案，极大地促进了Imperialine的实际使用。我们开始的基于脂质体的系统将极大地增强imperialine的治疗效果，同时在细胞模型和NSCLC模型中均表现出极低的副作用。这项工作已将Imperialine确定为一种有前途的新型抗癌化合物，并提供了一种有效的靶标传递解决方案，极大地促进了Imperialine的实际使用。我们开始的基于脂质体的系统将显着增强imperialine的治疗效果，同时在细胞模型和NSCLC模型中均表现出极低的副作用。这项工作已确定Imperialine是一种有前途的新型抗癌化合物，并提供了一种有效的靶标传递解决方案，极大地促进了Imperialine的实际使用。

"点击查看英文标题和摘要"

Mechanistic and therapeutic study of novel anti-tumor function of natural compound imperialine for treating non-small cell lung cancer.

ETHNOPHARMACOLOGICAL RELEVANCE Bulbus Fritillaria cirrhosa D. Don (BFC) is a Chinese traditional herbal medicine that has long been used as an indispensable component in herbal prescriptions for bronchopulmonary diseases due to its well-established strong anti-inflammation and pulmonary harmonizing effects. Interestingly, there are few case reports in traditional Chinese medicine available where they found it to contribute in anti-tumor therapies. Imperialine is one of the most favored active substances extracted from BFC and has been widely recognized as an anti-inflammatory agent. AIM OF THE STUDY The aim of the current work is to provide first-hand evidences both in vitro and in vivo showing that imperialine exerts anti-cancer effects against non-small cell lung cancer (NSCLC), and to explore the molecular mechanism of this anti-tumor activity. It is also necessary to examine its systemic toxicity, and to investigate how to develop strategies for feasible clinical translation of imperialine. MATERIALS AND METHODS To investigate anti-NSCLC efficacy of imperialine using both in vitro and in vivo methods where A549 cell line were chosen as in vitro model NSCLC cells and A549 tumor-bearing mouse model was constructed for in vivo study. The detailed underlying anti-cancer mechanism has been systematically explored for the first time through a comprehensive set of molecular biology methods mainly including immunohistochemistry, western blot and enzyme-linked immunosorbent assays. The toxicity profile of imperialine treatments were evaluated using healthy nude mice by examining hemogram and histopathology. An imperialine-loaded liposomal drug delivery system was developed using thin film hydration method to evaluate target specific delivery. RESULTS The results showed that imperialine could suppress both NSCLC tumor and associated inflammation through an inflammation-cancer feedback loop in which NF-κB activity was dramatically inhibited by imperialine. The NSCLC-targeting liposomal system was successfully developed for targeted drug delivery. The developed platform could favorably enhance imperialine cellular uptake and in vivo accumulation at tumor sites, thus improving overall anti-tumor effect. The toxicity assays revealed imperialine treatments did not significantly disturb blood cell counts in mice or exert any significant damage to the main organs. CONCLUSIONS Imperialine exerts anti-cancer effects against NSCLC both in vitro and in vivo, and this previously unknown function is related to NF-κB centered inflammation-cancer feedback loop. Imperialine mediated anti-cancer activity is not through cytotoxicity and exhibit robust systemic safety. Furthermore, the liposome-based system we commenced would dramatically enhance therapeutic effects of imperialine while exhibiting extremely low side effects both on cellular and in NSCLC model. This work has identified imperialine as a promising novel anti-cancer compound and offered an efficient target-delivery solution that greatly facilitate practical use of imperialine.

更新日期：2019-11-01

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