自噬在抗肿瘤药物毒性中的作用与机制研究进展

自噬是真核细胞中高度保守的依赖于溶酶体的胞内降解途径,在众多生理病理过程中发挥重要作用。随着对自噬关键基因与信号通路的深入解析,自噬与抗肿瘤药物毒性之间的关系也逐渐被揭示。抗肿瘤药物作为一类毒性和副作用相对较大的药物,在治疗肿瘤的同时常引起其他脏器系统的损伤。在某些抗肿瘤药物毒性中,自噬可作为一种保护机制减少损伤,但持续或过度的自噬激活亦可导致细胞死亡,诱发毒性。综述自噬发生的调控机制、生理病理作用,着重关注其在抗肿瘤药物毒性中的作用与机制,这将增进对自噬在抗肿瘤药物毒性中发挥的作用的全面认识,有助于发现自噬角色转变的关键要素,为抗肿瘤药物毒性的治疗和基于毒性机制的创新药物研发提供新思路与新靶点。     

自噬介导mTOR抑制剂抗肿瘤作用的研究进展

目的:为研发基于哺乳动物雷帕霉素靶蛋白(mTOR)信号通路调控肿瘤细胞自噬的新型抗肿瘤药物提供参考。方法:根据文献,对细胞自噬在肿瘤细胞生长中的作用、mTOR信号对细胞自噬的调节及自噬介导mTOR抑制剂的抗肿瘤作用等方面进行综述。结果:在营养不充分条件下细胞自噬作用可导致肿瘤细胞对化疗或放射治疗耐受;在肿瘤初期自噬限制肿瘤形成,在肿瘤后期自噬则为肿瘤细胞提供能量,促进细胞存活。mTOR的复合体mTOR复合体1(mTORC1)信号参与自噬体的诱导及形成,起负性调控细胞自噬的作用;在营养缺失下,mTOR调节细胞自噬是通过引发mTORC1失活而完成,且mTOR主要作用于自噬的起始阶段。抑制mTOR活性,诱导产生细胞自噬,促使细胞自噬性死亡,不仅能降低毒蛋白压力,也能起到抗肿瘤作用。结论:激活mTOR及其上游信号分子能诱导细胞自噬的产生,mTOR抑制剂及上游分子抑制剂(如磷脂酰肌醇3激酶抑制剂和蛋白激酶B抑制剂)具有明显的抗肿瘤作用。以mTOR为靶标调控细胞自噬形成,在抗肿瘤研究方面取得了较快的进展。进一步明确mTOR通路与细胞自噬关联的分子机制,可为寻找与研发新型靶向抗肿瘤药物提供新的思路。     

抗肿瘤药物与p53基因介导的抗肿瘤作用

抗肿瘤药物与ｐ５３基因介导的抗肿瘤作用魏小龙茹祥斌（军事医学科学院毒物药物研究所，北京１００８５０）１９９６－１０－１０收稿，１９９７－０３－１７修回作者简介：魏小龙，男，３２岁，博士研究生；茹祥斌，男，５８岁，研究员，副所长中国图书分类号Ｒ３４；Ｒ...     

细胞自噬的研究进展

本文综述了细胞自噬概念的研究现状、自噬与凋亡、自噬与肿瘤的关系,展望了自噬在抗癌药物介导的细胞死亡中发挥的重要作用以及自噬现象的临床意义.     

细胞凋亡与自噬在心血管疾病中的作用研究

摘 要细胞凋亡与自噬是普遍存在于各种细胞内的生命现象,广泛参与了机体的生理、病理过程,且二者有着多因子、多通路的相互影响,这种错综复杂的关系贯穿于各种心血管疾病的始终,对多种心血管疾病的发生发展转归起重要作用。现对细胞凋亡与自噬及其相互关系进行梳理,并综述其在心血管疾病中的作用。     

新型棉酚衍生物Apogossypolone的抗肿瘤作用研究概况

目的:为进一步研究新型棉酚衍生物Apogossypolone(Apo G2)的抗肿瘤作用提供参考。方法:以"Apogossypolone""Anti-tumor""棉酚衍生物"等为关键词,组合查询2008年1月至2015年5月中国知网、Pub Med和Springer Link等数据库中有关Apo G2抗肿瘤的文献并加以分析,了解Apo G2针对不同类别肿瘤的抗肿瘤机制与概况。结果与结论:共查阅到文献40篇,其中有效文献31篇。研究表明,Apo G2是一种新型、广谱和具有抗肿瘤活性的棉酚衍生物,其作用机制主要是通过改变凋亡和自噬相关基因来诱导细胞凋亡、自噬的发生。随着与Apo G2抗肿瘤有关的机制和治疗方法不断被发现,包括抑制肿瘤供血血管生成、活性氧依赖途径、光动力疗法、放射增敏等,这一系列研究在实验室阶段取得了突破性进展,可为Apo G2临床抗肿瘤应用提供参考。     

自噬在糖尿病中的作用

自噬是真核细胞在其生长、发育、老化过程中存在的一个降解和再循环系统。自噬通过调节蛋白质的合成和降解以及细胞器的更新来维持细胞稳态,而自噬机制的扰乱会导致多种急、慢性疾病如肿瘤、退行性疾病的发生。     

土槿皮乙酸对人肺癌A146细胞的自噬作用以及凋亡与自噬的关系

目的土槿皮乙酸是从松科植物金钱松的根皮或近根树皮中分离的二萜酸,具有抗肿瘤、抗生育等作用。本研究主要阐述了土槿皮乙酸能够诱导人肺癌细胞(A146)发生自噬从而抑制细胞生长的机制及在A146细胞中自噬与凋亡的关系。方法采用了形态学观察、四甲基偶氮唑蓝(MTT)分析法、MDC流式细胞术分析、MDC荧光染色法、乳酸脱氢酶LDH活力测试法、免疫沉淀法、蛋白质印迹法等方法考察了土槿皮乙酸通过自噬抑制A146细胞生长以及该细胞中自噬与凋亡的关系。结果研究发现,4μmol/L土槿皮乙酸作用A146细胞0、12、24、36、48 h后,细胞数目减少,MDC染色有荧光亮绿色颗粒出现,流式细胞仪分析显示土槿皮乙酸增加MDC阳性率。而且4μmol/L土槿皮乙酸作用后自噬相关蛋白Beclin 1的表达增高,LC3从Ⅰ型转化为Ⅱ型,说明土槿皮乙酸诱导A146细胞自噬,自噬在抑制A146细胞生长中起到了关键的作用。另外,加入自噬抑制剂3-MA与土槿皮乙酸联用之后,凋亡小体明显增加,凋亡率上升,自噬率下降,自噬相关蛋白Beclin 1和LC3表达降低,说明在A146细胞中,自噬是对抗凋亡的。结论土槿皮乙酸诱导A146细胞自噬,自噬在抑制A146细胞生长中起到了关键的作用。     

药物对细胞自噬性死亡的干预作用

近年来,分子生物学和基因组学等实验手段的快速发展,带动了细胞自噬性死亡的分子基础研究,虽然药物与细胞自噬性死亡关系的研究尚处于探索阶段,但已受到各领域学者的日益关注。本文从细胞自噬性死亡的分类、自噬体的检测方法及部分药物对细胞自噬性死亡的影响等方面,概述近年药物干预不同类型细胞自噬性死亡的研究。     

肿瘤多药耐药与自噬的研究进展

肿瘤多药耐药（multidrug resistance,MDR）对肿瘤的药物治疗的疗效有严重的影响。多药耐药拥有十分复杂的发生发展的机制。通过讨论自噬与药物抗肿瘤时的相互影响,旨在阐明自噬与肿瘤细胞多药耐药的关系,为今后抗肿瘤药物治疗的临床应用提供新的思路。     

Essential role of autophagy in fucoxanthin-induced cytotoxicity to human epithelial cervical cancer HeLa cells

Aim： To investigate the effects and the molecular mechanisms of fucoxanthin, a major carotenoid found in edible seaweed, on HeLa cells. Methods： The cytotoxicity of fucoxanthin was evaluated using MTT assay. Cell cycle and apoptosis were evaluated using flow cytometric analysis. Autophagy was detected with acridine orange staining and transient transfection of the GFP-LC3 plasmid into the cells. Protein expression was detected with Western blotting. Results： Treatment of HeLa cells with fucoxanthin （10-80 μmol/L） for 48 h caused dose-dependent cytotoxicity with an IC50 value of 55.1±7.6 μmol/L. Fucoxanthin （10, 20, and 40 pmol/L） dose-dependently induced Go/G1 arrest, but did not change the apoptosis of HeLa cells. The same concentrations of fucoxanthin dose-dependently increased the protein expression of LC3 II （the autophagosome marker） and Beclin 1 （the initiation factor for autophagosome formation） in HeLa cells. Moreover, fucoxanthin dose-dependently decreased the levels of phosphorylated Akt and its downstream proteins p53, p7OS6K, and mTOR, and increases the expression of PTEN in HeLa cells. Pretreatment of HeLa cells with 3-methyladenine （5 mmol/L） blocked the cytotoxic effect of fucoxanthin as well as fucoxanthin-induced autophagy. Conclusion： Fucoxanthin exerts autophagy-dependent cytotoxic effect in HeLa cells via inhibition of Akt/mTOR signaling pathway.     

抗肿瘤金属配合物药物及其药理作用的研究进展

自从顺铂作为抗肿瘤药物被开发利用以来,无机金属配合物药物已成为新的一类抗癌化疗药物。该文参阅国内外相关文献,介绍抗肿瘤铂及其它金属配合物药物的抗肿瘤机制及其药理作用,对抗肿瘤金属配合物药物的研究进展进行综述。     

Fucoxanthin treatment inhibits nasopharyngeal carcinoma cell proliferation through induction of autophagy mechanism

Nasopharyngeal carcinoma (NPC) arises from the epithelium of the nasopharyngeal mucosa. Elderly people above the age of 65 years are more susceptible to NPC. Nasopharyngectomy is the renowned treatment procedure to NPC; however, it is too risky due to its complicated surgical procedure. Other treatment methods also reported with serious side effects such brain injury; hence, the alternative anticancer drug without any side effects was needed. Fucoxanthin is a carotenoid derived from marine algae with the numerous pharmacological functions. This study aims to examine the inhibitory potential in NPC cell proliferation via apoptosis and autophagy. The cytotoxicity of fucoxanthin on C666‐1 cells was observed by the MTT assay. The expression of autophagy‐linked proteins was assessed with immunoblotting analysis. The expression of autophagy protein LC3 was estimated using immunocytochemical analysis in C666‐1 and GFP‐LC3 transfected cells. Furthermore, the fucoxanthin‐treated C666‐1 cells were analyzed with TUNEL assay. The apoptotic level in the fucoxanthin‐treated C666‐1 cells was evaluated using acridine orange staining. Fucoxanthin significantly increased the expression of autophagy‐linked proteins which is clearly depicted in the immunoblotting analysis and immunocytochemical analysis of GFP‐tagged LC3 protein. The results of TUNEL assay of fucoxanthin‐treated C666‐1 in the presence autophagy inhibitors demonstrated the induction of autophagy by fucoxanthin. Acridine orange staining results of C666‐1 confirmed fucoxanthin decreases the expression of autophagy‐linked proteins during stressed condition thereby causes apoptosis. Our overall results authentically conclude that fucoxanthin induces autophagy and apoptosis in NPC cell line, and it can be ideal agent to treat nasopharyngeal cancer in future with further investigations.     

抗肿瘤药物的治疗药物监测研究

尽管治疗药物监测(TDM)已广泛应用于多个疾病治疗领域,但在抗肿瘤药物方面的应用仍较为局限。近年来,抗肿瘤药物的暴露量与其疗效和药物不良反应之间的相关性研究越来越多,这有利于抗肿瘤药物个体化精准给药。本文综述了细胞毒类和靶向性(小分子和大分子)抗肿瘤药物的治疗药物监测现状,为肿瘤药物个体化用药提供参考。     

萘酰亚胺类化合物作为抗肿瘤药物的研发现状*

萘酰亚胺是一类具有良好抗肿瘤活性的化合物，主要分为单萘酰亚胺和双萘酰亚胺，处于临床研究阶段的分别有氨萘非特（amonafide）、米托萘胺（mitonafide）和依利萘法德（elinafide）、双萘法德（bisnafide）。具有抗肿瘤活性的萘酰亚胺类化合物大多是DNA嵌入剂，并且靶向拓扑异构酶Ⅱ。现以几个主要代表药物为例，介绍了萘酰亚胺类化合物的抗肿瘤活性、作用机制以及临床研究进展。     

The role of reduced intracellular concentrations of active drugs in the lack of response to anticancer chemotherapy

A major difficulty in the treatment of cancers is the poor response of many tumors to pharmacological regimens. This situation can be accounted for by the existence of a variety of complex mechanisms of chemoresistance （MOCs）, leading to reduced intracellular concentrations of active agents, changes in the molecular targets of the drugs, enhanced repair of drug-induced modifications in macromolecules, stimulation of anti-apoptotic mechanisms, and inhibition of pro-apoptotic mechanisms. The present review focuses on alterations in the expression and appearance of the genetic variants that affect the genes involved in reducing the amount of active agents inside tumor cells. These alterations can occur through two mechanisms： either by lowering uptake or enhancing efflux （so-called MOC-1a and MOC-1b, respectively）, or by decreasing the activation of prodrugs or enhancing inactivation of active agents through their biotransformation （MOC-2）. The development of chemosensitizers that are useful in implementing the pharmacological manipulation of these processes constitutes a challenge to modern pharmacology. Nevertheless, the important physiological roles of the most relevant genes involved in MOC-1a, MOC-1b, and MOC-2 make it difficult to prevent the side effects of chemosensitizers. A more attainable goal in this area of pharmacological enquiry is the identification of proteomic profiles that will permit oncologists to accurately predict a lack of response to a given regimen, which would be useful for adapting treatment to the personal situation of each patient.     

Cell cycle modulatory and apoptotic effects of plant-derived anticancer drugs in clinical use or development

Drugs derived from natural products, particularly from plants, are the leads of clinically used anticancer agents. Plant-derived anticancer agents in clinical use consist of the Vinca alkaloids, vinblastine and vincristine, camptothecin derivatives, paclitaxel, etoposide and teniposide, homoharringtonine and elliptinium. Extensive research has led to the identification of promising plant-derived anticancer agents in clinical development, namely flavopiridol, combretastatins and roscovitine. These compounds share common antitumor activities and signaling pathways targeting tumor cell cycle and cell death. This review presents the discovery of plant-derived anticancer agents, their biologic activities, with emphasis on cell cycle and apoptotic effects and combination strategies for treatment optimization.     

Polymeric micelles for targeted tumor therapy of platinum anticancer drugs

Introduction: Platinum anticancer drugs are effective against a wide range of tumors, though their severe adverse effects and resistance remain unresolved. A breakthrough in these drawbacks could be achieved by using polymeric micelles, i.e. nanoassemblies having a drug loaded core and a protective hydrophilic shell, incorporating platinum drugs for tumor-targeted delivery.

Areas covered: The development of cisplatin- (NC-6004) and DACHPt-loaded micelles (NC-4016) has been reviewed, particularly, from the viewpoint of the effect of their structural features on the tumor-targeting efficacy. We have also described new approaches for molecular targeting by installing ligand moieties on the surface of micelles. Moreover, small platinum drugs and platinum drug-loaded nanocarriers are introduced to explain the context for developing platinum drug-loaded polymeric micelles.

Expert opinion: NC-6004 and NC-4016 micelles meet critical structural and functional requirements for achieving safe and effective tumor targeting, enhancing efficacy even against drug resistant cancer cells, and have been translated into human studies, aiming to be the first-of-their-kind in the clinic. Due to their flexible design, polymeric micelles could readily integrate new features based on the knowledge arising from the human clinical trials toward the development of innovative formulations with superior performance.     

Promise and challenges in drug discovery and development of hybrid anticancer drugs

Background: Because cancer is a complex disease, it is unlikely that a single mono functional ‘targeted’ drug will be effective for treating this most advanced disease. Combined drugs that impact multiple targets simultaneously are better at controlling complex disease systems, are less prone to drug resistance and are the standard of care in cancer treatment. In order to improve the efficiency of using a two-drug cocktail, one approach involves the use of the so-called hybrid drugs, which comprises the incorporation of two drugs in a single molecule with the intention of exerting dual drug action.

Objective: In the present article, we discuss the design, synthesis and various applications of anticancer hybrid agents and the developments in this field during the last few decades. Additionally, we describe different types of linkers and their role in contributing towards biological effects and the in vivo mechanism of drug release. We also depict some challenges from scientific and regulatory perspectives in the hybrid drug development process.

Conclusion: In the era of increasing drug resistance in cancer patients, the discovery of hybrid drugs could provide an effective strategy to create chemical entities likely to be more efficacious and less prone to resistance. However, some technical and regulatory challenges will have to be surmounted before hybrid drugs succeed in the clinical settings and justify the considerable promise of this novel concept.