摘要
靶向硫酸乙酰肝素蛋白聚糖(HSPG)和参与硫酸乙酰肝素(HS)链编辑的酶正在成为新的抗癌策略。 HSPGs参与肿瘤细胞信号传导,炎症,血管生成和转移表明,能够抑制异常HSPG功能的药物可能潜在地作为影响肿瘤细胞生长和由微环境提供的支持性促进作用的多靶点药物。此外,积累的证据支持HSPGs或调节其活性的复合酶系统的改变的表达或功能也可以抑制肿瘤对几种肿瘤类型的抗癌治疗的反应。因此,靶向HSPG或HSPG修饰酶似乎是提高化疗疗效的有吸引力的方法。来自学术界和工业界的大量努力导致了模拟HS和/或抑制HSPG修饰酶的试剂的开发。 Sulf-2的抑制剂,编码HS硫酸化模式的内切硫酸酶,以及产生功能性HS片段的糖内切酶的乙酰肝素酶抑制剂似乎特别有希望。事实上,Sulf-2抑制剂(OKN-007)和两种肝素酶抑制剂/ HS模拟物(roneparstat,PG545)目前正在进行临床研究。在本综述中,我们总结了Sulf-2和乙酰肝素酶抑制剂主要化学类别实验性肿瘤模型的临床前研究。我们描述了通常合作的乙酰肝素酶和HSPG可能影响各种抗肿瘤剂对肿瘤敏感性的不同机制的实例。最后,我们报道了一些临床前研究,显示使用候选临床HS模拟物在组合方案中获得的增加的抗肿瘤功效。
关键词: 硫酸肝素蛋白聚糖,乙酰肝素酶,硫酸乙酰肝素模拟物,乙酰肝素酶抑制剂,硫酸酯酶抑制剂,抗癌药物抗药性,抗癌化疗。
Current Medicinal Chemistry
Title:Targeting Heparan Sulfate Proteoglycans and their Modifying Enzymes to Enhance Anticancer Chemotherapy Efficacy and Overcome Drug Resistance
Volume: 24 Issue: 26
关键词: 硫酸肝素蛋白聚糖,乙酰肝素酶,硫酸乙酰肝素模拟物,乙酰肝素酶抑制剂,硫酸酯酶抑制剂,抗癌药物抗药性,抗癌化疗。
摘要: Targeting heparan sulfate proteoglycans (HSPGs) and enzymes involved in heparan sulfate (HS) chain editing is emerging as a new anticancer strategy. The involvement of HSPGs in tumor cell signaling, inflammation, angiogenesis and metastasis indicates that agents able to inhibit aberrant HSPG functions can potentially act as multitarget drugs affecting both tumor cell growth and the supportive boost provided by the microenvironment. Moreover, accumulating evidence supports that an altered expression or function of HSPGs, or of the complex enzyme system regulating their activities, can also depress the tumor response to anticancer treatments in several tumor types. Thereby, targeting HSPGs or HSPG modifying enzymes appears an appealing approach to enhance chemotherapy efficacy. A great deal of effort from academia and industry has led to the development of agents mimicking HS, and/or inhibiting HSPG modifying enzymes. Inhibitors of Sulf-2, an endosulfatase that edits the HS sulfation pattern, and inhibitors of heparanase, the endoglycosidase that produces functional HS fragments, appear particularly promising. In fact, a Sulf-2 inhibitor (OKN-007), and two heparanase inhibitors/HS mimics (roneparstat, PG545) are currently under early clinical investigation. In this review, we summarized preclinical studies in experimental tumor models of the main chemical classes of Sulf-2 and heparanase inhibitors. We described examples of different mechanisms through which heparanase and HSPGs, often in cooperation, may impact tumor sensitivity to various antitumor agents. Finally, we reported a few preclinical studies showing increased antitumor efficacy obtained with the use of candidate clinical HS mimics in combination regimens.
Export Options
About this article
Cite this article as:
Targeting Heparan Sulfate Proteoglycans and their Modifying Enzymes to Enhance Anticancer Chemotherapy Efficacy and Overcome Drug Resistance, Current Medicinal Chemistry 2017; 24 (26) . https://dx.doi.org/10.2174/0929867324666170216114248
DOI https://dx.doi.org/10.2174/0929867324666170216114248 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Defective HIF Signaling Pathway and Brain Response to Hypoxia in Neurodegenerative Diseases: Not an “Iffy” Question!
Current Pharmaceutical Design The Rationale of Targeting Neutrophils with Dapsone during Glioblastoma Treatment
Anti-Cancer Agents in Medicinal Chemistry Opposing Functions for the Wilms Tumor Protein 1 (WT1) in Tumorigenesis
Current Pediatric Reviews Intramolecular Processes and Their Applications in Prodrugs Approaches- Experimental and Computational Studies
Current Organic Chemistry CYP24A1 as a Potential Target for Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Molecular Biotheranostic Approaches of Cancers Using LAT Kit Probes
Current Medical Imaging Covalently and Ionically Crosslinked Chitosan Nanogels for Drug Delivery
Current Pharmaceutical Design Epigenetic Regulators Governing Cancer Stem Cells and Epithelial- Mesenchymal Transition in Oral Squamous Cell Carcinoma
Current Stem Cell Research & Therapy Designing of Novel Carbonic Anhydrase Inhibitors and Activators
Current Medicinal Chemistry - Cardiovascular & Hematological Agents Recent Developments in Targeting Breast Cancer Stem Cells
Recent Patents on Regenerative Medicine A Bioinformatics Study of the Involved Mechanisms in Relapse and Drug Resistance of Tamoxifen-Treated Breast Cancer
Anti-Cancer Agents in Medicinal Chemistry Advances in Research on Pharmacological Activities and Synthesis of Oleanolic Acid Derivatives at C-3 Position
The Natural Products Journal P-glycoprotein as a Drug Target in the Treatment of Multidrug Resistant Cancer
Current Drug Targets The Synergistic Effect of Humanized Monoclonal Antibodies Targeting Insulin-Like Growth Factor 1 Receptor (IGF-1R) and Chemotherapy
Current Drug Targets Molecular and Cellular Activities of Vitamin E Analogues
Mini-Reviews in Medicinal Chemistry Targeted Blood-to-Brain Drug Delivery – 10 Key Development Criteria
Current Pharmaceutical Biotechnology In Vitro Biological Estimation of 1,2,3-Triazolo[4,5-d]pyrimidine Derivatives as Anti-breast Cancer Agent: DFT, QSAR and Docking Studies
Current Pharmaceutical Biotechnology Role of Antioxidants, Essential Fatty Acids, Carnitine, Vitamins, Phytochemicals and Trace Elements in the Treatment of Diabetes Mellitus and its Chronic Complications
Endocrine, Metabolic & Immune Disorders - Drug Targets The Molecular Basis of Herpesviruses as Oncolytic Agents
Current Pharmaceutical Biotechnology Importance of Wnt Signaling in the Tumor Stroma Microenvironment
Current Cancer Drug Targets