Chistiakov Dimitry A, Myasoedova Veronika A, Orekhov Alexander N, Bobryshev Yuri V
Department of Molecular Genetic Diagnostics and Cell Biology, Division of Laboratory Medicine, Institute of Pediatrics, Research Center for Children's Health, 119991 Moscow. Russian Federation.
Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow 125315. Russian Federation.
Curr Pharm Des. 2017;23(8):1167-1174. doi: 10.2174/1381612822666161021110827.
Epigenetic mechanisms, which are involved in the regulation of gene expression, are tightly controlled. Loss of a proper epigenetic control can lead to global epigenetic alterations frequently observed in various diseases including cancer. Aberrant epigenetic changes induced in malignant cells lead to emergence of neoplastic properties, which inhibit cell differentiation and strict cell cycle control but greatly enhance stemness-related features. However, abnormal epigenetic patterns can be reversed by action of epigenetically active agents. Epigenetic machinery comprises a variety DNA/histone modifiers and chromatin remodelers. Chemical substances able to influence on the activity of epigenetic factors such as inhibitors of DNA methyltransferases or histone deacetylase inhibitors can be used as therapeutic agents for improving aberrant epigenetic signatures in cancer cells. Preclinical studies showed efficiency of such epigenetic drugs for the treatment of variety of cancers. So far, several epigenetically active compounds were approved for therapy of hematological malignancies. However, many challenges should be resolved for efficient use of epidrugs in the treatment of non-hematological solid tumors and advanced cancers associated with chemoresistance and higher risk of relapse.
参与基因表达调控的表观遗传机制受到严格控制。适当的表观遗传控制的丧失会导致在包括癌症在内的各种疾病中经常观察到的全局表观遗传改变。恶性细胞中诱导的异常表观遗传变化导致肿瘤特性的出现，这抑制细胞分化和严格的细胞周期控制，但极大地增强了与干性相关的特征。然而，异常的表观遗传模式可以通过表观遗传活性剂的作用来逆转。表观遗传机制包括多种DNA/组蛋白修饰剂和染色质重塑剂。能够影响表观遗传因子活性的化学物质，如DNA甲基转移酶抑制剂或组蛋白脱乙酰酶抑制剂，可作为治疗剂用于改善癌细胞中异常的表观遗传特征。临床前研究表明此类表观遗传药物对多种癌症的治疗有效。到目前为止，几种表观遗传活性化合物已被批准用于治疗血液系统恶性肿瘤。然而，要在治疗非血液系统实体瘤以及与化疗耐药性和更高复发风险相关的晚期癌症中有效使用表观遗传药物，还需要解决许多挑战。
