Histone Deacetylase Inhibitors in Cancer Therapy
Histone Deacetylase Inhibitors in Cancer Therapy
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DOI：
10.4161/cbt.190
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发表时间：
2003-01
影响因子：
3.6
通讯作者：
R. Rosato;S. Grant
中科院分区：
文献类型：
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作者：
R. Rosato;S. Grant
组蛋白去乙酰化酶抑制剂（HDAC抑制剂）代表一类新的通过促进组蛋白乙酰化而起作用的抑制剂，其继而导致染色质的解螺旋和参与调节细胞存活、增殖、分化和凋亡的多种基因的激活。HDI的主要类别包括短链脂肪酸、异羟肟酸衍生物、合成苯甲酰胺衍生物和环四肽。这些类别中的每一个成员现在都已进入人体临床试验。尽管它们具有触发组蛋白去乙酰化的共同能力，但单个HDIs对细胞周期调节、信号转导和存活相关蛋白发挥不同的作用，这很可能是它们不同作用的原因。围绕HDIs的主要研究领域包括阐明它们诱导肿瘤细胞凋亡的机制，以及表征负责决定这些细胞响应于这些药剂而经历成熟与细胞死亡的因素。在这种情况下，注意力最近集中在HDI诱导细胞周期调节蛋白（例如，p21 CIP 1），下调存活信号传导途径（例如，Raf/MEK/ERK）和细胞氧化还原状态的破坏（例如，活性氧物质的诱导; ROS）。除了将联合收割机HDI与已建立的细胞毒性药物组合的努力之外，正在尝试建立将HDI与分化诱导剂（例如，ATRA、低甲基化剂如5 ′-脱氧氮杂胞苷），其目的是触发肿瘤抑制基因和/或分化相关基因的再表达。最后，最近的临床前研究结果为HDIs与其他新型分子靶向药物（包括生存信号通路或细胞周期进展抑制剂）的联合应用提供了有力的理论依据。总的来说，这些发现应该为未来许多年在癌症治疗中开发新的含HDI方案提供肥沃的环境。
Histone deacetylase inhibitors (HDAC inhibitors) represent a novel class of antineoplastic agents that act by promoting acetylation of histones, leading in turn to uncoiling of chromatin and activation of a variety of genes implicated in the regulation of cell surivival, proliferation, differentiation, and apoptosis. The major classes of HDIs include short-chain fatty acids, hydroxamic acid derivatives, synthetic benzamide derivatives, and cyclic tetrapeptides. Members of each of these classes have now entered clinical trials in humans. Despite their shared capacity to trigger histone deacetylation, individual HDIs exert diverse actions on cell cycle regulatory, signal transduction, and survival-related proteins which in all probability accounts for their disparate actions. Major areas of investigation surrounding HDIs include elucidating the mechanisms by which they induce apoptosis in neoplastic cells, and characterizing the factors responsible for the decision of such cells to undergo maturation versus cell death in response to these agents. In this context, attention has recently focused on the ability of HDIs to induce perturbations in cell cycle regulatory proteins (e.g., p21CIP1), downregulation of survival signaling pathways (e.g., Raf/MEK/ERK), and disruption of cellular redox state (e.g., induction of reactive oxygen species; ROS). Aside from efforts to combine HDIs with established cytotoxic drugs, attempts are underway to establish a rational basis for combining HDIs with differentiation-inducing agents (e.g., ATRA, hypomethylating agents such as 5'-deoxyazacytine) with the goal of triggering re-expression of tumor suppressor and/or differentiation-associated genes. Finally, the results of recent preclinical studies provide a strong rationale for combining HDIs with other novel, molecularly targeted agents, including inhibitors of survival signaling pathways or cell cycle progression. Collectively, these findings should provide a fertile environment for the development of novel HDI-containing regimens in the treatment of cancer for many years to come.