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。     

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，     

Livin与消化道肿瘤

细胞凋亡一直是肿瘤研究的热点，肿瘤的发生不仅和细胞过度增生有关，同时也和凋亡减少有很大的关系。细胞凋亡机制非常复杂，其过程受到严密的多方面控制。胱氨酸蛋白酶（caspases）的级联激活是凋亡过程的关键环节之一。Bel-2家族蛋白和IAPs家族蛋白是控制Caspases蛋白酶激活的主要因素。某些IAPs成员异常高表达常引起组织细胞凋亡受阻，与肿瘤的发生密切相关。Livin是新近发现的一个IAP家族成员，与多种肿瘤的发生密切相关。我们就其分子生物学特性、抗细胞凋亡作用机制以及与消化道肿瘤的关系等研究现状作一介绍。     

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。     

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,     

Livin——癌症治疗的新靶点

Livin是IAPs(inhibitorsofapoptosisproteins,IAPs)蛋白家族的新成员 ,有BIR和RING指结构域 ,能够与Caspas es蛋白结合 ,抑制其介导的细胞凋亡。它在大多数正常成人组织中不表达、在一些肿瘤细胞中的高表达 ,与肿瘤的关系为人们所关注 ,是肿瘤治疗的潜在靶点。     

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。     

Livin Caspase-9与胃癌关系的研究进展

胃癌的发生、发展是一个多因素、多基因相互作用的复杂过程,如RAS基因家族、MYC基因家族、ERBB基因家族、p53、RB等^[1,2]。Livin是IAPs（inhibitors of apoptosis proteins）蛋白家族的新成员^[3],能够与Caspases蛋白结合,抑制其介导的细胞凋亡。     

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。     

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。     

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.     

凋亡抑制蛋白的研究进展

近年来新发现的凋亡抑制蛋白(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.IAPs主要通过抑制caspase,参与TNFR介导的信号转导等途径发挥抗凋亡作用,与恶性肿瘤、神经系统病变等密切相关.该文就IAPs的结构、抑制凋亡的机制及其在临床疾病中的研究现状作一综述.     

Predominant enhancement of apoptosis induced by methyl jasmonate in bladder cancer cells: therapeutic effect of the Antp-conjugated Smac peptide

Methyl jasmonate (MJ) has recently attracted attention as a promising antitumoral compound because of its highly specific proapoptotic properties in a wide range of malignancies. However, the high doses required to achieve a therapeutic benefit have limited its clinical development. Here, we hypothesize that the family of inhibitor of apoptosis proteins (IAPs) may inhibit MJ-mediated apoptosis in cancer cells. We combined MJ with the IAPs inhibitor, the second mitochondria-derived activator of caspases (Smac) peptide to treat bladder cancer cells. The results showed that the combination of MJ and Smac peptide enhanced the apoptosis-inducing effect in a synergistic manner by releasing and activating IAPs-bounding caspase-3. These findings suggest that the inhibition of IAPs could overcome the resistance of cancer cells to MJ.     

Smac/DIABLO and colon cancer

Apoptosis is a genetically programmed process of controlled and orderly cell suicide, which is critical for multicellular organisms during development and tissue homeostasis. In cancer, the ratio of apoptosis to cell division is altered, resulting in a net gain of malignant tissue. Tumor cells may acquire resistance to apoptosis by the expression of anti-apoptotic proteins, or by the down-regulation or mutation of pro-apoptotic mediators. In the classic pathway of apoptosis, this process is primarily coordinated by activation of caspases. Decreased expression of caspases inversely correlates with the aggressiveness of cancer. Increased activity of caspases renders cancer cells susceptible to chemoradiotherapeutic modalities. Thus, caspase activity is pivotal in carcinogenesis. The functions of activated caspases are inhibited by the binding of inhibitors of apoptosis (IAPs). The function of IAPs is regulated by pro-apoptotic protein Second Mitochondria-Derived Activator of Caspases (Smac) or Direct IAP Binding Protein with low isoelectric point, pI (DIABLO). Induction of apoptosis leads to increased mitochondrial permeability to Smac/DIABLO, which adheres to IAPs inhibiting their caspase-binding activity. The role of Smac/DIABLO, therefore, may have significant diagnostic and therapeutic features in carcinogenesis. The role of Smac/DIABLO in colorectal carcinogenesis is ill defined. Data continues to accumulate to suggest that decreased levels of Smac/DIABLO may be important in chemoradiation-resistance to apoptosis in advanced colon cancer. The aim of this review is to provide the available evidence of the role of Smac/DIABLO in colon carcinogenesis.     

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.     

Targeting endogenous inhibitors of apoptosis for treatment of cancer, stroke and multiple sclerosis

The inhibitor of apoptosis (IAP) genes have emerged as probably the most important intrinsic regulators of apoptosis. The members of the IAP family are highly conserved in evolutionarily distant species and perform the critical role of binding to and inhibiting distinct caspases. This inhibition is mediated by discrete baculoviral IAP repeat domains that, in a domain-specific manner, inhibit either the initiator or executioner caspases. As such the function of IAPs lies at the very centre of virtually all apoptotic pathways. Since many, if not most, human pathologies involve aberrant apoptosis, the modulation of IAP levels or their activity offers huge therapeutic potential for treatment of various disorders. Indeed, available data suggest that the therapeutic downregulation of IAPs by antisense targeting or their adenovirally-mediated overexpression, can in fact be used to successfully modulate cell death.     

Targeting endogenous inhibitors of apoptosis for treatment of cancer,stroke and multiple sclerosis

The inhibitor of apoptosis (IAP) genes have emerged as probably the most important intrinsic regulators of apoptosis. The members of the IAP family are highly conserved in evolutionarily distant species and perform the critical role of binding to and inhibiting distinct caspases. This inhibition is mediated by discrete baculoviral IAP repeat domains that, in a domain-specific manner, inhibit either the initiator or executioner caspases. As such the function of IAPs lies at the very centre of virtually all apoptotic pathways. Since many, if not most, human pathologies involve aberrant apoptosis, the modulation of IAP levels or their activity offers huge therapeutic potential for treatment of various disorders. Indeed, available data suggest that the therapeutic downregulation of IAPs by antisense targeting or their adenovirally-mediated overexpression, can in fact be used to successfully modulate cell death.     

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.