Herr I, Debatin K M
Division of Pediatric Oncology, German Cancer Research Center, Heidelberg, Germany.
Blood. 2001 Nov 1;98(9):2603-14. doi: 10.1182/blood.v98.9.2603.
Anticancer treatment using cytotoxic drugs is considered to mediate cell death by activating key elements of the apoptosis program and the cellular stress response. While proteolytic enzymes (caspases) serve as main effectors of apoptosis, the mechanisms involved in activation of the caspase system are less clear. Two distinct pathways upstream of the caspase cascade have been identified. Death receptors, eg, CD95 (APO-1/Fas), trigger caspase-8, and mitochondria release apoptogenic factors (cytochrome c, Apaf-1, AIF), leading to the activation of caspase-9. The stressed endoplasmic reticulum (ER) contributes to apoptosis by the unfolded protein response pathway, which induces ER chaperones, and by the ER overload response pathway, which produces cytokines via nuclear factor-kappaB. Multiple other stress-inducible molecules, such as p53, JNK, AP-1, NF-kappaB, PKC/MAPK/ERK, and members of the sphingomyelin pathway have a profound influence on apoptosis. Understanding the complex interaction between different cellular programs provides insights into sensitivity or resistance of tumor cells and identifies molecular targets for rational therapeutic intervention strategies.
使用细胞毒性药物的抗癌治疗被认为是通过激活凋亡程序的关键要素和细胞应激反应来介导细胞死亡的。虽然蛋白水解酶（半胱天冬酶）是凋亡的主要效应器，但半胱天冬酶系统激活所涉及的机制尚不清楚。已确定了半胱天冬酶级联上游的两条不同途径。死亡受体，如CD95（APO-1/Fas），触发半胱天冬酶-8，而线粒体释放凋亡诱导因子（细胞色素c、凋亡蛋白酶激活因子-1、凋亡诱导因子），导致半胱天冬酶-9的激活。应激的内质网通过诱导内质网伴侣的未折叠蛋白反应途径和通过核因子-κB产生细胞因子的内质网过载反应途径促进凋亡。多种其他应激诱导分子，如p53、JNK、AP-1、NF-κB、PKC/MAPK/ERK和鞘磷脂途径的成员对凋亡有深远影响。了解不同细胞程序之间的复杂相互作用有助于深入了解肿瘤细胞的敏感性或抗性，并确定合理治疗干预策略的分子靶点。
