文章：

杀死癌症：有什么替代方案？

Killing a cancer: what are the alternatives?

原文发布日期：2012-05-11

DOI: 10.1038/nrc3264

类型: Review Article

开放获取: 否

要点：

1. A number of alternative cell death programmes, such as necroptosis, lysosomal-mediated programmed cell death (LM-PCD) and autophagy have been established alongside classical apoptosis. These are now known to act both as a backup to apoptosis and also as preferred death pathways in certain cell types.
2. Necroptosis can be triggered by a RIP1- and RIP3-containing complex. This complex can form downstream of death receptors or in the cytosol following stress stimuli. It is tightly regulated by the initiator caspase 8, as well as inhibitors of apoptosis (IAPs) and FLICE-like inhibitory protein (FLIP). Hence, caspase inhibitors, as well as second mitochondria-derived activator of caspases (SMAC) mimetics, are strong sensitizers for necroptosis.
3. LM-PCD, which occurs because of a loss of lysosomal integrity, is frequently seen in cancer cells. This is due to increased metabolism and protein turnover, as well as a reduction of important lysosomal structural proteins. Cancer cells are thus particularly responsive to drugs that target the lysosomes, and drugs ranging from lysosomotropic agents to monoclonal antibodies and microtubule-disrupting agents have all been shown to induce LM-PCD.
4. Autophagy can have both tumour suppressive and tumour-promoting activities. Large-scale autophagy can eventually lead to cell death; however, it is not clear precisely how this type of death is induced. Inhibition and induction of autophagy have both proved to be beneficial under certain circumstances, and the decision as to whether inhibition or activation is preferable is still largely empirical.
5. The alternative pathways of cell death prove to be intricately interconnected with many points of convergence, such as JUN N-terminal kinase (JNK), AMP-activated protein kinase (AMPK) or reactive oxygen species (ROS). Necroptosis has LM-PCD as a frequent downstream occurrence, and an impaired lysosomal compartment affects the ability of autophagosomes to mature. These converging and diverging features are increasingly better understood, leading to a number of targeted approaches aimed at these alternative pathways.

要点翻译：

1. 除了经典的细胞凋亡外，目前已确立多种替代性细胞死亡程序，如坏死性凋亡、溶酶体介导的程序性细胞死亡（LM-PCD）和自噬。这些程序既可作为细胞凋亡的备份机制，也是特定细胞类型中的优先死亡途径。
2. 坏死性凋亡可由包含RIP1和RIP3的复合体触发。该复合体可在死亡受体下游或细胞质中响应应激刺激而形成，并受到起始 caspase 8、凋亡抑制蛋白（IAPs）以及FLICE样抑制蛋白（FLIP）的精密调控。因此，caspase抑制剂及第二线粒体衍生caspase激活剂（SMAC）模拟物能显著增强坏死性凋亡的敏感性。
3. LM-PCD由溶酶体完整性丧失引发，常见于癌细胞。这归因于代谢增强、蛋白质周转加速以及关键溶酶体结构蛋白减少。癌细胞对靶向溶酶体的药物尤为敏感，从溶酶体趋向剂到单克隆抗体和微管破坏剂等多种药物均被证实可诱导LM-PCD。
4. 自噬兼具抑癌和促癌双重功能。大规模自噬最终可能导致细胞死亡，但其诱导机制尚未明确。自噬的抑制与诱导在特定情况下均被证明具有治疗价值，但目前选择抑制或激活仍主要依赖经验判断。
5. 这些替代性细胞死亡通路通过JUN N末端激酶（JNK）、AMP活化蛋白激酶（AMPK）或活性氧（ROS）等多个交汇点形成复杂互连网络。坏死性凋亡常伴随下游LM-PCD发生，而溶酶体功能受损会影响自噬体成熟能力。随着对这些交叉与分化特征的深入理解，针对这些替代通路的多项靶向治疗方案正在不断推进。

英文摘要：

Evading programmed cell death is one of the hallmarks of cancer. Conversely, inducing cell death by pharmacological means is the basis of almost every non-invasive cancer therapy. Research over the past decade has greatly increased our understanding of non-apoptotic programmed cell death events, such as lysosomal-mediated cell death, necroptosis and cell death with autophagy. It is becoming clear that an intricate effector network connects many of these classical and non-classical death pathways. In this Review, we discuss converging and diverging features of these pathways, as well as attempts to exploit this newly gained knowledge pharmacologically to provide therapeutics for cancer.

摘要翻译： 

逃避程序性细胞死亡是癌症的特征之一。相反，通过药理学手段诱导细胞死亡几乎是所有非侵入性癌症治疗的基础。过去十年的研究极大地增进了我们对非凋亡性程序性细胞死亡事件的理解，例如溶酶体介导的细胞死亡、坏死性凋亡以及伴随自噬的细胞死亡。越来越明确的是，一个复杂的效应网络将这些经典和非经典的死亡通路连接起来。在本综述中，我们讨论了这些通路的趋同与分化特征，以及尝试利用这些新获得的知识进行药理学干预，以提供癌症治疗手段。

原文链接：

Killing a cancer: what are the alternatives?