以IAPs为靶点的抗肿瘤研究进展

凋亡抑制因子(inhibitor of apoptosis proteins,IAPs)是一类高度保守的内源性抗细胞凋亡因子家族,主要通过抑制caspase活性和参与调节核因子NF-κB的作用抑制细胞凋亡。caspases蛋白酶的级联激活是凋亡过程的中心环节,Bcl-2家族蛋白和IAPs家族蛋白是主要控制因素。近年来发现,某些IAPs成员异常表达与肿瘤密切相关,成为肿瘤治疗的潜在靶点。因此,该文主要综述了与IAPs家族相关的蛋白以及以IAPs为靶点的抗肿瘤研究。     

X连锁凋亡抑制蛋白与肿瘤关系的研究进展

XIAP(连锁凋亡抑制蛋白)是凋亡抑制蛋白家族中最强的内源性的抑制因子,其可以通过不同的信号转导通路及调控相关凋亡蛋白酶的表达产生抗凋亡作用。研究发现其与肿瘤的发生、发展有着密切的关系,已经成为许多肿瘤的治疗靶点。凋亡抑制蛋白家族的组成成分是细胞内源性的凋亡抑制蛋白,目前,共发现有16种此类蛋白,其中的8个是人类的IAPs家族成员:它们是XIAP、c-IAP1、c-IAP2、神经凋亡抑制蛋白、存活素、BRUCE、ML-IAP、ILP-2等。XIAP是IAPs家族中最具有效力的半胱氨酸天冬氨酸蛋白酶的抑制物,具有极强的抗凋亡作用。     

凋亡抑制蛋白的研究进展

凋亡抑制蛋白（inhibitor of apoptosis proteins．IAPs），是一类高度保守的内源性抗凋亡基因家族表达产物．广泛存在于许多物种如病毒、真核生物、哺乳动物中，起着抑制细胞凋亡的作用。目前已报道该家族成员有十多种，如NAIP、XIAP、Survivin、BRUCE和Livin等。IAPs主要有三个结构域（BIR、RING与CARD结构域），共有单位BIR域能与其它基序连接，非BIR区能使IAPs的功能多样化或调节IAP家族蛋白的表达。IAPs主要通过caspase蛋白酶激活级联反应途径及肿瘤坏死因子受体（TNFR）介导的信号转导途径抑制细胞凋亡，     

姜黄素抗肿瘤作用机制的研究进展

多种恶性肿瘤细胞中表达细胞凋亡抑制蛋白（IAPs）,如：Survivin、NAIP、XIAP、Livin等,同样表达抗细胞凋亡Bcl-2家族蛋白。IAPS介导的凋亡抑制可能是肿瘤细胞耐药而存活的原因之一;Bcl-2家族蛋白在抗肿瘤凋亡及促其凋亡中发挥作用。姜黄素具有抗炎、抗氧化、抑制血管新生等,可以通过调控蛋白表达及相关信号通路促进细胞凋亡、抗肿瘤作用。     

细胞凋亡抑制蛋白-2研究进展

细胞凋亡抑制蛋白-2（inhibitor of apoptosis protein-2）基因是细胞凋亡抑制蛋白（IAPs）家族重要组成部分,属于抗凋亡基因。编码细胞凋亡抑制蛋白-2,可与多种细胞因子作用,抑制细胞凋亡。研究提示细胞凋亡抑制蛋白-2在诊断肿瘤、判断预后、选择治疗方法以及保护正常细胞方面具有重要作用。本文对近年来C-IAP2的研究作一综述。     

肺癌外周血中Survivin mRNA表达及其对预后的判断价值

<正>Survivin是新近发现的凋亡抑制蛋白(IAP)家族中新的一员,其抗凋亡作用的机制可通过Caspase途径和非Caspase途径实现,属于一种结构独特的哺乳类凋亡抑制蛋白(IAPs)家族成员,Survivin同时具有肿瘤组织特异性高表达的特性,研究已证实多种常见肿瘤如胃癌、大肠癌、     

XIAP与慢性粒细胞白血病耐药的研究进展

XIAP是凋亡抑制蛋白(IAPs)家族中最重要的抗凋亡蛋白,可以通过抑制Caspases活性,参与调节受体介导的信号转导和蛋白泛素化等细胞功能活动,从而对抗细胞凋亡。抗凋亡机制的增强可以使肿瘤细胞产生凋亡逃逸现象,从而诱导多药耐药的发生。慢性粒细胞白血病的靶向药物是研究热点,但随着药物的广泛应用,耐药基因型也逐渐增多。本文综述XIAP在慢性粒细胞白血病耐药过程中的作用及相关机制,为通过调节XIAP表达靶向治疗耐药型慢性粒细胞白血病患者提供理论依据。     

Survivin、xiap、apollon和livin反义寡核苷酸对人消化系肿瘤细胞增殖及凋亡的影响

目的观察凋亡抑制蛋白(inhibitor of apoptosis proteins,IAPs)家族survivin、xiap、apollon和livin反义寡核苷酸(antisense oligodeoxynucleotide,ASO)对人消化系肿瘤细胞增殖、凋亡的影响。方法人工合成survivin、xiap、apol-lon、livin的反义核酸和随机序列,经脂质体包裹后作用肝癌细胞、胃癌细胞、结肠癌细胞48 h后,采用WST-8法观察对细胞增殖的影响,流式细胞术检测细胞凋亡率。结果 IAPs ASO作用于肝癌HepG2细胞、胃癌MGC-803细胞、结肠癌Lovo细胞48 h后,与空白对照组(control)和随机寡核苷酸(random oligodeoxynucleotide,RODN)对照组相比,IAPs ASO能明显抑制肝癌细胞、胃癌细胞、结肠癌细胞的增殖和诱导细胞凋亡(P<0.01)。其中,在作用浓度为0.2μmol.L-1时,survivin ASO对HepG2、Lovo细胞的增殖抑制率最高,分别为84.2%、82.6%。xiap ASO对MGC-803细胞的增殖抑制率最高,为86.56%,并呈时间-剂量依赖效应。survivin ASO诱导Lovo细胞、MGC-803细胞凋亡作用最强,凋亡率为34.95%、27.6%,livin ASO诱导HepG2细胞凋亡作用最强,凋亡率为27.4%。结论针对凋亡抑制蛋白家族survivin、xiap、apollon、livin的反义核酸均能有效抑制消化系肿瘤细胞增殖,并诱导细胞凋亡。     

生长抑素促进肿瘤细胞凋亡机制的研究进展

生长抑素及其类似物具有明确的促进肿瘤细胞凋亡的作用,其具体机制研究正在不断丰富完善中。新近发现的凋亡抑制蛋白家族（IAPs）已经成为肿瘤细胞凋亡研究的新热点。本文将就上述问题作一综述。     

Livin和Smac的相关性研究进展

Livin蛋白是凋亡抑制蛋白家族IAPs的新成员,其主要功能是通过BIR区与胱天蛋白酶Caspase-3,7,9结合并抑制其活性,从而抑制细胞凋亡。Smac是从线粒体膜间区释放入细胞质的重要凋亡调节因子,     

Inhibitors of Apoptotic Proteins: New Targets for Anticancer Therapy

Inhibitors of apoptotic proteins (IAPs) can play an important role in inhibiting apoptosis by exerting their negative action on caspases (apoptotic proteins). There are eight proteins in this family: NAIP/BIRC1/NLRB, cellular IAP1 (cIAP1)/human IAP2/BIRC2, cellular IAP2 (cIAP2)/human IAP1/BIRC3, X‐linked IAP (XIAP)/BIRC4, survivin/BIRC5, baculoviral IAP repeat (BIR)‐containing ubiquitin‐conjugating enzyme/apollon/BIRC6, livin/melanoma‐IAP (ML‐IAP)/BIRC7/KIAP, and testis‐specific IAP (Ts‐IAP)/hILP‐2/BIRC8. Deregulation of these inhibitors of apoptotic proteins (IAPs) may push cell toward cancer and neurodegenerative disorders. Inhibitors of apoptotic proteins (IAPs) may provide new target for anticancer therapy. Drugs may be developed that are inhibiting these IAPs to induce apoptosis in cancerous cells.     

Targeting inhibitor of apoptosis proteins (IAPs) for cancer therapy

Since cell death by apoptosis plays a key role in the regulation of tissue homeostasis, dysregulation of the cell's intrinsic death program may foster tumor formation and progression. "Inhibitor of apoptosis proteins" (IAPs) block apoptosis at the core of the apoptotic machinery by inhibiting effector caspases. Aberrant expression and/or function of IAPs are found in many human cancers and have been implied in resistance to current treatment approaches. Recent insights into the role of IAPs have provided the basis for various exciting discoveries that aim at modulating expression or function of IAPs. Thus, targeting IAPs, e.g. by antisense approaches or small molecule inhibitors, presents a promising novel approach for future drug development and may proof to be a successful strategy to overcome apoptosis resistance of human cancers.     

Targeting inhibitor of apoptosis proteins (IAPs) for diagnosis and treatment of human diseases

Since cell death by apoptosis plays a key role in the regulation of tissue homeostasis, any defect in this intrinsic death program may result in tumor formation. "Inhibitor of apoptosis proteins" (IAPs) block apoptosis at the core of the apoptotic machinery by inhibiting effector caspases. Aberrant expression and/or function of IAPs have been implied to be involved in the pathogenesis and progression of various human diseases including cancer, autoimmune disorders or neurodegeneration. Recent insights into the regulation of IAPs have provided the basis for various exciting discoveries aimed at modulating expression or dysfunction of IAPs. Thus, targeting IAPs, e.g. by antisense approaches, RNA interference or small molecules, may proof to be a novel strategy for the diagnosis and treatment of human diseases.     

Betulinic acid induces apoptotic and autophagic cell death in hepatocellular carcinoma

Betulinic acid, a natural product, was extracted from a broad range of Chinese medicinal herbs. Subsequent researches show when subjected to betulinic acid, tumours derived from multiple tissues manifest apoptotic features. This study aims to investigate the role of betulinic acid in apoptosis and autophagy of hepatocellular carcinoma(HCC) as well as the crosstalk between betulinic acid-induced apoptotic and autophagic cell death. We employed luciferase-tagged hepatoma cell line MHCC97L to establish orthotopic HCC implanted mice. Hepatocellular carcinoma cells PLC/PRF/5 and MHCC97L were used as in vitro models. The apoptotic mechanism behind betulinic acid function was examined using flow cytometry, immunoblotting, and real-time PCR techniques. Autophagic regulation was monitored by transmission electron microscopy, fluorescence spectroscopy, and MTT assays. We found that betulinicacid induced targeted degradation of inhibitor of apoptosis proteins(IAPs) family(cIAP-1, cIAP-2, XIAP and survivin),which are generally overexpressed in tumours. Meanwhile, autophagy was modulated in betulinic acid-treated hepatoma cellsas evidenced by induction of autophagic flux. Administration of autophagy inhibitor had no significant influence on molecules associated with apoptosis(IAPs), but could reversebetulinic acid-induced hepatoma cell death. Above all, the mode of action underlying betulinic acid-induced anti-cancer efficacy in vitro and in vivo was due, at least in part, to autophagy activation as well as pro-apoptotic responses mediated by modulation of IAPs family.     

Solid-phase synthesis of smac peptidomimetics incorporating triazoloprolines and biarylalanines

Apoptotic induction mechanisms are of crucial importance for the general homeostasis of multicellular organisms. In cancer the apoptotic pathways are downregulated, which, at least partly, is due to an abundance of inhibitors of apoptosis proteins (IAPs) that block the apoptotic cascade by deactivating proteolytic caspases. The Smac protein has an antagonistic effect on IAPs, thus providing structural clues for the synthesis of new pro-apoptotic compounds. Herein, we report a solid-phase approach for the synthesis of Smac-derived tetrapeptide libraries. On the basis of a common (N-Me)AVPF sequence, peptides incorporating triazoloprolines and biarylalanines were synthesized by means of Cu(I)-catalyzed azide-alkyne cycloaddition and Pd-catalyzed Suzuki cross-coupling reactions. Solid-phase procedures were optimized to high efficiency, thus accessing all products in excellent crude purities and yields (both typically above 90%). The peptides were subjected to biological evaluation in a live/dead cellular assay which revealed that structural decorations on the AVPF sequence indeed are highly important for cytotoxicity toward HeLa cells.     

Anti-tumor therapeutic molecules that target the programmed cell death machinery

Apoptosis is a process that governs the elimination of unwanted, damaged, or infected cells in most organisms. Defects in its execution are associated with several diseases, including cancer. Herein, we discuss novel molecules with potential anti-tumor activity that target components of the apoptotic machinery, specifically Bcl-2 proteins, IAPs and caspases.     

Role of genomics-based strategies in overcoming chemotherapeutic resistance

As cancer is being recognized as a failure of apoptosis, apoptosis-based strategies are being designed. Caspases are critical for the induction of apoptosis and their decreased expression is correlated with increased grade of cancer, while increased expression of caspases rendered the cancer cells susceptible to chemotherapy. However, the endogenous functions of caspases are inhibited by inhibitors of apoptosis (IAPs) that bind activated caspases. Methods to suppress the function of IAP induced apoptosis in chemo-resistant cancer cells. The function of IAPs is inhibited by Second Mitochondria-Derived Activator Of Caspase (Smac) or Direct IAP Binding Protein With Low Pi (DIABLO). Upon apoptotic stimulus Smac/DIABLO is released from the mitochondria, which binds to IAPs and inhibits their caspase-binding activity. Overexpression of Smac/DIABLO sensitized neuroblastoma to TRAIL (TNFalpha-Related Apoptosis-Inducing Ligand). Activation of TRAIL pathway has become an important method of inducing apoptosis except in TRAIL-resistant cells. However, treatment of these cells with other cytotoxic drugs sensitizes them to TRAIL, providing effective therapeutic advantages. In addition to activating apoptotic pathways, inhibiting or suppression of cell proliferation is necessary to sensitize cancer cells to apoptosis. Critical among these proteins are NFkappaB and Akt. NFkappaB blocked apoptosis by interfering with the function of TNFalpha/TRAIL and/or through the activation of antiapoptotic proteins of the Bcl2 family. Similarly, Akt mediate cell survival via the regulation of cell survival proteins and by blocking the function of proapoptotic Bad by phosphorylation. Altering the expression of Akt by dominant negative constructs or by expression of PTEN interferes with Akt function. In summary, this review points out the complexity of interactions of the cell survival and death pathways and highlights some methods to manipulate them to achieve therapeutic advantage.     

Altering protein turnover in tumor cells: New opportunities for anti-cancer therapies

The promising effects of the proteasome inhibitor bortezomib (Velcade, PS-341) in the treatment of certain types of cancer have fired up the interest on this multicatalytic proteolytic machinery. A number of recent reviews thoroughly describe various aspects of the ubiquitin-proteasome system and its importance in the control of cell growth and tumorigenesis. Here, we will focus on recent data unveiling a link between the proteasome and some elements of the apoptotic machinery including Bcl-2 members, caspases, IAPs and IAP antagonists. Perturbing their turnover significantly contributes to the apoptotic response and the anti-neoplastic activity of proteasome inhibitors.     

Apoptotic death sensor: an organelle's alter ego?

Caspases are intracellular cysteine proteases that are primarily responsible for the stereotypic morphological and biochemical changes that are associated with apoptosis. Caspases are often activated by the apoptotic protease-activating factor 1 (APAF-1) apoptosome, a complex that is formed following mitochondrial release of cytochrome c in response to many death-inducing stimuli. Both pro- and anti-apoptotic BCL-2 family members regulate apoptosis, primarily by their effects on mitochondria, whereas many inhibitor of apoptosis proteins (IAPs) regulate apoptosis by directly inhibiting distinct caspases. Exposure of cells to chemicals and radiation, as well as loss of trophic stimuli, perturb cellular homeostasis and, depending on the type of cellular stress, particular or multiple organelles appear to 'sense' the damage and signal the cell to undergo apoptosis by stimulating the formation of unique and/or common caspase-activating complexes.     

细胞凋亡抑制蛋白(IAPs)与肿瘤治疗的策略

凋亡是维持机体稳定的重要过程，其功能失调与多种疾病的发生有关。IAPs家族蛋白参与凋亡的调节，与肿瘤的关系受到人们的关注。本对近年来IAPs家族蛋白和以其某些成员为靶点的抗癌策略的研究进展作一概述。