低氧诱导因子在肿瘤干细胞介导的肿瘤发生发展中的作用

低氧及低氧诱导因子（HIFs）是肿瘤干细胞、 转移起始细胞及其分化后代在肿瘤发生发展过程中, 能够适应氧气和营养物质缺乏的主要调节因子。在白血病、 胶质母细胞瘤、 黑色素瘤、 前列腺癌、 乳腺癌、 胰腺癌等肿瘤中均发现 HIFs 的表达上调, 尤其集中表达在低氧区域。活化的 HIFs 可以诱导多种干性及多药耐药等基因的表达, 对肿瘤及干性介导的肿瘤细胞的自我更新、 能量代谢改变、 侵袭转移、 血管生成以及治疗抵抗均起着重要作用。因此, 研究 HIFs 分子在干细胞介导的不同肿瘤细胞中的靶向调节作用和代谢通路的改变, 将为肿瘤的靶向治疗提供新线索。     

缺氧诱导因子-1调控转录及相关转录抑制剂的研究进展

细胞低氧适应性反应可通过转录调节蛋白——缺氧诱导因子-1（HIF-1)和p300/CBP辅激动因子对低氧应答基因的转录激活介导。HIF-1是药学上重要的靶点，设计以HIF-1α/300复合物为靶点的小分子转录抑制剂，可用于心脑血管疾病或肿瘤的治疗。本文就HIF-1α与p300的相互作用，以及氧依赖的特殊氨基酸羟化对HIF-1α蛋白稳定性和转录激活调控的研究进展作一综述。     

低氧诱导因子脯氨酰羟化酶抑制剂的研究进展

目的 综述低氧诱导因子脯氨酰羟化酶抑制剂的研究进展。方法 查找近年低氧诱导因子脯氨酰羟化酶抑制剂的相关文献,对已上市脯氨酰羟化酶抑制剂罗沙司他、伐度司他和达普司他等,正在进行临床试验的在研药物以及新型结构的脯氨酰羟化酶抑制剂进行了归纳和总结。结果与结论脯氨酰羟化酶抑制剂用于治疗慢性肾脏病引起的贫血,与传统药物相比具有很多优点,已经成为了当前研究热点。此外,发现新型结构的脯氨酰羟化酶抑制剂也是重点研究方向之一。     

缺氧反应元件同肿瘤治疗的研究进展

研究表明,在肿瘤适应低氧过程中缺氧诱导因子（HIF）起着中枢纽带作用,HIF是肿瘤适应低氧,产生一系列低氧行为的中心环节,而最近研究发现,缺氧反应元件（hypoxia response elements,HRE）是介导细胞低氧反应的重要调控序列,HRE是一种缺氧敏感诱导性调控元件,在实体瘤内的活性较高,在肿瘤细胞生长、浸润及转移等过程中发挥着重要的作用。     

脯氨酸羟化酶抑制剂的研究进展

低氧诱导因子(hypoxia-inducible factor,HIF)是细胞适应低氧环境的关键性转录因子,在组织贫(缺)血和炎症性疾病中稳定表达,对缓解病情具有重要作用。脯氨酸羟化酶(proline hydroxylase domain,PHD)能实现HIF的羟基化,是体内降解HIF的最主要蛋白酶。PHD抑制剂可以有效增加体内HIF蛋白含量,对于贫血及炎症性疾病治疗具有积极意义。本研究对小分子PHD抑制剂的最新进展进行综述。     

血液系统／造血器官及免疫药物：11073 Asteiias获得治疗贫血化合物的权利

Astellas公司已经从美国生物技术公司获得两种治疗贫血化合物的权利。 根据最新协议条款，Astellas公司将获得FG-2216和FG-4592（两种Fibrogen公司研发的口服治疗贫血的药物）以及其他具有相似作用机制的化合物。这些化合物可抑制脯氨酰羟化酶，该酶介导低氧诱导因子的降解，而低氧诱导因子是促红细胞生成素（EPO）产生的关键。     

低氧诱导因子与铁代谢紊乱促肿瘤发展研究进展

肿瘤是威胁人类生命健康的严重疾病。低氧诱导因子（HIF）及铁代谢紊乱与肿瘤发展密切相关。铁是人体必需的微量元素,其含量受铁代谢相关蛋白调控。一般缺铁上调HIF表达,而HIF通过调控铁代谢相关蛋白以改变机体各部位铁含量。铁代谢紊乱和HIF上调促进肿瘤细胞增殖、迁移、侵袭及能量代谢异常,促进肿瘤血管生长,抑制肿瘤免疫微环境,从而促进肿瘤的发生与发展。联合使用铁离子螯合剂和HIF抑制剂能够显著增强其抗肿瘤作用,靶向铁代谢与HIF途径可能为肿瘤的研究与治疗提供新思路。     

低氧诱导因子-1的病理生理及相关药物研究进展

低氧诱导因子-1（hypoxia-inducible factors, HIF-1）是介导哺乳动物和人体细胞低氧适应性反应的主要核转录因子,是专一调节氧稳态的关键物质。 HIF-1对胚胎的正常发育,软骨及骨的形成等多种生理过程起保护及促进作用,也与肿瘤、糖尿病及其并发症等多种缺血低氧性疾病密切相关。 HIF-1在这些疾病中的分子机制已成为目前的研究热点,笔者就HIF-1的结构特征、调控机制、生物学效用及在药物研发等方面进行综述。     

基于低氧微环境的小分子激活前药与HIF-1抑制剂研究进展

低氧是实体瘤普遍存在的特征,是肿瘤细胞增殖、转移、侵袭、产生放疗抗性的重要原因。因此,肿瘤缺氧被认为是肿瘤诊断与治疗的一个重要靶点。低氧激活前药可在缺氧微环境下通过电子还原靶向低氧区域的肿瘤细胞,产生并释放细胞毒性代谢产物,从而杀死肿瘤细胞。目前已报道的低氧激活前药主要包括硝基化合物、醌类、氮氧化物、金属配合物、偶氮化合物五大类。而低氧诱导因子-1(hypoxia-inducible factor-1,HIF-1)也在肿瘤细胞的低氧存活与发展中扮演重要角色,抑制HIF-1可抑制其下游基因主导的肿瘤血管生成、转移、耐药等生存发展进程。当前,已有低氧激活前药与HIF-1抑制剂正处于临床试验阶段,并表现出良好的抗肿瘤活性,并有可能在未来的肿瘤诊断与治疗中发挥重要作用。     

血管生成因子与肿瘤血管生成和抑制的研究

近年来肿瘤血管生成已经成为肿瘤学研究的一个重要领域,迄今,人们已经发现了大约12种有血管生成活性的因子,这些因子可通过一种或几种不同的途径来诱导血管生成。本文总结了这些血管生成因子及其促血管生成的研究新进展,同时也对血管生成抑制剂的研究作了简述。     

Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2011-2015)

Introduction: Hypoxia-inducible factor (HIF)-1α regulates the expression of genes involved in angiogenesis, cellular energy metabolism, and cell survival during cancer development. The increased expression of HIF-1α in most solid tumors is associated with poor prognoses and therapeutic outcomes. Therefore, HIF has been recognized as an attractive target for cancer therapy, and many HIF inhibitors have been reported.

Areas covered: This patent survey summarizes the information about patented HIF inhibitors over the last 5 years (2011–2015).

Expert opinion: Although many of the HIF inhibitors reviewed in this patent survey possess inhibitory activity against cancer and HIF-related diseases, the compounds are still in the early stages of development, most likely due to the complexity of the HIF-1 pathway and their different mechanisms of action for HIF inhibition. Most cancer cells use the glycolytic pathway for energy production and HIF-1α participates deeply in the expression of several glycolytic enzymes. Therefore, a detailed study of HIF’s function in cancer metabolisms may provide us an alternative strategy for further development of HIF inhibitors in cancer therapy.     

HIF,hypoxia and the role of angiogenesis in non-small cell lung cancer

Importance of the field: The role of angiogenesis in the initiation and progression of NSCLC and the molecular alterations leading to the growth of tumor vasculature are areas of great interest and recent therapeutic success.

Areas covered in this review: VEGF and its receptors play critical roles in the development of tumor vasculature and can be targeted by agents such as bevacizumab in the treatment of NSCLC. Furthermore, tumor hypoxia and the expression of the hypoxia-inducible factor (HIF) family of proteins are also linked to poorer survival in these patients. Recent studies using genetically engineered mouse models expressing stabilized HIF validate the importance of HIF in the evolution of NSCLC and demonstrate genetically that HIF is involved in NSCLC.

What the reader will gain: An overview of the key pathways and mediators of tumor angiogenesis, their relevance to the pathogenesis of NSCLC, and an update on the current status of angiogenesis inhibitors in NSCLC.

Take home message: Angiogenesis is a key mediator of NSCLC progression. Several antiangiogenic strategies are in clinical use and under development. While candidate predictive biomarkers of response to antiangiogenic therapy exist, they await independent and prospective validation.     

Pathophysiological response to hypoxia - from the molecular mechanisms of malady to drug discovery: drug discovery for targeting the tumor microenvironment

The tumor microenvironment, characterized by regions of hypoxia, low nutrition, and acidosis due to incomplete blood vessel networks, has been recognized as a major factor that influences not only the response to conventional anti-cancer therapies but also malignant progression and metastasis. However, exploiting such a cumbersome tumor microenvironment for cancer treatment could provide tumor-specific therapeutic approaches. In particular, hypoxia is now considered a fundamentally important characteristic of the tumor microenvironment in which hypoxia inducible factor (HIF)-1-mediated gene regulation is considered essential for angiogenesis and tumor development. Additional oxygen sensitive signaling pathways including mammalian target of rapamycin (mTOR) signaling and signaling through activation of the unfolded protein response (UPR) also contribute to the adaptation in the tumor microenvironment. This in turn has led to the current extensive interest in the signal molecules related to adaptive responses in the tumor microenvironment as potential molecular targets for cancer therapy against refractory cancer and recurrence in preparation for the aging society. Therefore, we should focus on the drug discovery for targeting the tumor microenvironment to develop tumor-specific cytostatic agents including angiogenesis inhibitors. In this paper, the development of hypoxia-selective prodrugs, HIF-1 inhibitors, and modulators of the tumor microenvironment will be discussed.     

Hypoxia-regulated microRNAs in human cancer

Hypoxia plays an important role in the tumor microenvironment by allowing the development and maintenance of cancer cells, but the regulatory mechanisms by which tumor cells adapt to hypoxic conditions are not yet well understood. MicroRNAs are recognized as a new class of master regulators that control gene expression and are responsible for many normal and pathological cellular processes. Studies have shown that hypoxia inducible factor 1 (HIF1) regulates a panel of microRNAs, whereas some of microRNAs target HIF1. The interaction between microRNAs and HIF1 can account for many vital events relevant to tumorigenesis, such as angiogenesis, metabolism, apoptosis, cell cycle regulation, proliferation, metastasis, and resistance to anticancer therapy. This review will summarize recent findings on the roles of hypoxia and microRNAs in human cancer and illustrate the machinery by which microRNAs interact with hypoxia in tumor cells. It is expected to update our knowledge about the regulatory roles of microRNAs in regulating tumor microenvironments and thus benefit the development of new anticancer drugs.     

缺氧诱导因子与炎症及肿瘤的关系

局部微环境缺氧是炎症和恶性肿瘤的共同特征。缺氧使细胞触发适应性反应导致缺氧诱导因子(HIF)过度表达。该文在扼要叙述其结构与功能的基础上,探讨HIF与炎症和肿瘤的关系。