Pirola Luciano, Ciesielski Oskar, Balcerczyk Aneta
INSERM U1060, 165 Ch. du Grand Revoyet-BP12, 69921 Oullins, France.
Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland.
Cancers (Basel). 2018 Aug 10;10(8):268. doi: 10.3390/cancers10080268.
Approximately 50 years ago, Judah Folkman raised the concept of inhibiting tumor angiogenesis for treating solid tumors. The development of anti-angiogenic drugs would decrease or even arrest tumor growth by restricting the delivery of oxygen and nutrient supplies, while at the same time display minimal toxic side effects to healthy tissues. Bevacizumab (Avastin)-a humanized monoclonal anti VEGF-A antibody-is now used as anti-angiogenic drug in several forms of cancers, yet with variable results. Recent years brought significant progresses in our understanding of the role of chromatin remodeling and epigenetic mechanisms in the regulation of angiogenesis and tumorigenesis. Many inhibitors of DNA methylation as well as of histone methylation, have been successfully tested in preclinical studies and some are currently undergoing evaluation in phase I, II or III clinical trials, either as cytostatic molecules-reducing the proliferation of cancerous cells-or as tumor angiogenesis inhibitors. In this review, we will focus on the methylation status of the vascular epigenome, based on the genomic DNA methylation patterns with DNA methylation being mainly transcriptionally repressive, and lysine/arginine histone post-translational modifications which either promote or repress the chromatin transcriptional state. Finally, we discuss the potential use of "epidrugs" in efficient control of tumor growth and tumor angiogenesis.
大约50年前，朱达·福克曼提出了通过抑制肿瘤血管生成来治疗实体瘤的概念。抗血管生成药物的研发将通过限制氧气和营养物质的供应来减少甚至阻止肿瘤生长，同时对健康组织显示出最小的毒副作用。贝伐单抗（阿瓦斯汀）——一种人源化抗VEGF - A单克隆抗体——目前被用作多种癌症的抗血管生成药物，但效果各异。近年来，我们对染色质重塑和表观遗传机制在血管生成和肿瘤发生调控中的作用有了重大进展。许多DNA甲基化以及组蛋白甲基化的抑制剂已在临床前研究中成功测试，有些目前正在进行I期、II期或III期临床试验评估，它们要么作为抑制癌细胞增殖的细胞毒性分子，要么作为肿瘤血管生成抑制剂。在这篇综述中，我们将基于基因组DNA甲基化模式（DNA甲基化主要具有转录抑制作用）以及赖氨酸/精氨酸组蛋白翻译后修饰（其可促进或抑制染色质转录状态），重点关注血管表观基因组的甲基化状态。最后，我们讨论“表观药物”在有效控制肿瘤生长和肿瘤血管生成方面的潜在用途。
