Attacking c-Myc: Targeted and Combined Therapies for Cancer
Attacking c-Myc: Targeted and Combined Therapies for Cancer
复制标题
攻击 c-Myc：癌症的靶向联合治疗
DOI：
10.2174/1381612820666140826153203
复制
发表时间：
2014-01-01
影响因子：
3.1
通讯作者：
Qu, Lianghu
中科院分区：
文献类型：
--
作者：
Huang, Huilin;Weng, Hengyou;Qu, Lianghu
癌症的发生是一个复杂的过程，由多种基因突变的积累驱动。然而，由于癌细胞的“癌基因成瘾”，抑制单个癌基因可以损害癌细胞的增殖和存活的事实为癌症治疗中的所谓“分子靶向治疗”提供了启示。致癌转录因子c-Myc在许多类型的癌症中过表达，并且作为许多癌症所依赖的典型癌基因，c-Myc对于癌细胞的快速增殖是必需的。靶向c-Myc的策略，包括干扰c-Myc的合成、稳定性和转录活性，已经成为有效的癌症治疗方法。我们最近发现，一种天然药物，冬凌草甲素，促进Fbw 7介导的c-Myc蛋白酶体降解，导致随后的细胞生长抑制和凋亡，并证明了一种新的c-Myc靶向策略。尽管分子靶向在癌症治疗中是有效的，但观察到用单一药剂未能实现持久的功效，因为癌细胞由于其基因组不稳定性和异质性而可以从癌基因成瘾中恢复。因此，开发了联合癌症疗法，并在癌细胞系和小鼠模型中显示出比单药疗法更好的疗效。基于c-Myc靶向的联合治疗可以通过各种策略实现。可以选择也靶向c-Myc但使用不同机制的药剂或作用于c-Myc途径中的其他基因的药剂进行组合。此外，靶向参与其他途径中不同细胞过程的基因也可能是一种成功的策略。无论采用哪种疗法，重要的是首先确定药物的分子机制，以指导治疗设计。在治疗剂的各种靶点中，有一个非编码小RNA家族，称为microRNA，其与许多治疗剂的抗癌活性有关。c-Myc作为一种转录因子，调节许多microRNA的表达，反过来又受microRNA的调节。将c-Myc靶向药物与靶向microRNA的药物结合可能为癌症治疗提供一种新的方法。
The onset of cancer is a complex process that is driven by the accumulation of multiple genetic mutations. However, the fact that inhibition of a single oncogene can impair the proliferation and survival of cancer cells due to their "oncogene addiction" provides implications for the so-called "molecular targeted therapy" in cancer treatment. The oncogenic transcription factor c-Myc is overexpressed in many types of cancers, and as a typical oncogene to which many cancers are addicted, c-Myc is necessary for the rapid proliferation of cancer cells. Strategies aimed at targeting c-Myc, including interfering with c-Myc synthesis, stability and transcriptional activity, have emerged as effective cancer treatments. We have recently shown that a natural agent, oridonin, promotes the Fbw7-mediated proteasomal degradation of c-Myc, leading to subsequent cell growth inhibition and apoptosis and demonstrating a new c-Myc-targeting strategy. Despite the effectiveness of molecular targeting in cancer treatment, failure to achieve long-lasting efficacy with a single agent is observed because cancer cells can recover from oncogene addiction as a result of their genomic instability and heterogeneity. Combined cancer therapies were therefore developed and showed better efficacies than single-agent therapy in cancer cell lines and mouse models. Combined therapy based on c-Myc targeting can be achieved through various strategies. Agents that also target c-Myc but use different mechanisms, or agents that act on other genes in the c-Myc pathway, can be selected for combination. In addition, the targeting of genes involved in different cellular processes in other pathways might also be a successful strategy. Regardless of the therapy adopted, it is important to first determine the molecular mechanisms underlying the agents to inform the therapy design. Among the various targets of therapeutic agents is a family of noncoding small RNAs, called microRNAs, that have been implicated in the anti-cancer activity of many therapeutic agents. c-Myc, as a transcription factor, regulates the expression of many microRNAs and is in turn regulated by microRNAs. Combining c-Myc-targeting agents with those that target microRNAs might provide a novel approach for cancer therapy.