Apoptosis-targeted therapies for cancer
Apoptosis-targeted therapies for cancer
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DOI：
10.1016/s1535-6108(02)00241-6
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发表时间：
2003-01-01
期刊：
影响因子：
50.3
通讯作者：
Reed, JC
中科院分区：
文献类型：
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作者：
Reed, JC
程序性细胞死亡（细胞凋亡）机制的缺陷在肿瘤发病机制中发挥着重要作用，使肿瘤细胞能够存活超过其正常预期的寿命，颠覆对外源生存因子的需求，在肿瘤肿块扩大时提供免受缺氧和氧化应激的保护，并允许累积的基因改变放松细胞增殖，干扰分化，促进血管生成，并在肿瘤进展过程中增加细胞运动性和侵袭性（Reed，1999）。事实上，细胞凋亡缺陷被认为是原癌基因激活的重要补充，因为许多驱动细胞分裂的失调癌蛋白也会引发细胞凋亡（例如，Myc、E1a、Cyclin-D1）（Green 和 Evan，2002）。同样，DNA 修复和染色体分离的缺陷通常会触发细胞自杀，作为根除遗传不稳定细胞的防御机制，因此细胞凋亡缺陷允许遗传不稳定的细胞存活，为选择渐进攻击性克隆提供机会（Ionov 等，2000）。细胞凋亡缺陷还通过允许上皮细胞以悬浮状态存活而不附着于细胞外基质来促进转移（Frisch和Screaton，2001）。它们还促进对免疫系统的抵抗，因为许多用于攻击肿瘤的溶细胞 T 细胞 (CTL) 和自然杀伤 (NK) 细胞武器都依赖于细胞凋亡机制的完整性（Tschopp 等，1999）。最后，与癌症相关的细胞凋亡缺陷在化学抗性和放射抗性中发挥作用，增加了细胞死亡的阈值，从而需要更高的剂量来杀死肿瘤（Makin 和 Hickman，2000）。因此，有缺陷的细胞凋亡调节是癌症生物学的一个基本方面。当谈到通过非手术手段成功根除癌细胞时，最终，所有途径都会导致细胞凋亡。基本上目前临床使用的所有细胞毒性抗癌药物在发挥作用时都会诱导恶性细胞凋亡。虽然微管结合药物、DNA损伤剂和核苷是治疗癌症的重要武器，但基于对细胞凋亡现象背后的分子机制的深入了解而产生的策略，一类新型靶向治疗药物可能很快就会出现。细胞凋亡是由称为“半胱天冬酶”的蛋白酶引起的，即半胱氨酸天冬氨酰特异性蛋白酶（Cryns 和 Yuan，1999；Thornberry 和 Lazebnik，1998）。 Caspases 构成细胞内半胱氨酸蛋白酶家族（人类中 n = 11），它们在蛋白水解级联中协作，其中 Caspases 激活自身和彼此。在这些蛋白水解级联中，半胱天冬酶可以定位为细胞凋亡的上游“启动子”或下游“效应子”。存在多种激活半胱天冬酶的途径（图 1）。首先，是的？肿瘤坏死因子 (TNF) 家族受体有 30 个成员，其中 8 个在其胞质尾部含有所谓的死亡结构域 (DD)（Locksley 等，2001）。其中一些含有 DD 的 TNF 家族受体
Defects in programmed cell death (apoptosis) mechanisms play important roles in tumor pathogenesis, allowing neoplastic cells to survive beyond their normally intended lifespans, subverting the need for exogenous survival factors, providing protection from hypoxia and oxidative stress as tumor mass expands, and allowing time for accumulative genetic alterations that deregulate cell proliferation, interfere with differentiation, promote angiogenesis, and increase cell motility and invasiveness during tumor progression (Reed, 1999). In fact, apoptosis defects are recognized as an important complement to protooncogene activation, as many deregulated oncoproteins that drive cell division also trigger apoptosis (eg, Myc, E1a, Cyclin-D1)(Green and Evan, 2002). Similarly, defects in DNA repair and chromosome segregation normally trigger cell suicide as a defense mechanism for eradicating genetically unstable cells, and thus apoptosis defects permit survival of genetically unstable cells, providing opportunities for selection of progressively aggressive clones (Ionov et al., 2000). Apoptosis defects also facilitate metastasis by allowing epithelial cells to survive in a suspended state, without attachment to extracellular matrix (Frisch and Screaton, 2001). They also promote resistance to the immune system, inasmuch as many of the weapons cytolytic T cells (CTLs) and natural killer (NK) cells use for attacking tumors depend on integrity of the apoptosis machinery (Tschopp et al., 1999). Finally, cancer-associated defects in apoptosis play a role in chemoresistance and radioresistance, increasing the threshold for cell death and thereby requiring higher doses for tumor killing (Makin and Hickman, 2000). Thus, defective apoptosis regulation is a fundamental aspect of the biology of cancer.When it comes to the successful eradication of cancer cells by nonsurgical means, ultimately, all roads lead to apoptosis. Essentially all cytotoxic anticancer drugs currently in clinical use, when they work, induce apoptosis of malignant cells. While microtubule binding drugs, DNA-damaging agents, and nucleosides are important weapons in the treatment of cancer, a new class of targeted therapeutics may soon be forthcoming based on strategies that have emerged from a deeper understanding of the molecular mechanisms that underlie the phenomenon of apoptosis. Apoptosis is caused by proteases known as “caspases,” for cysteine aspartyl-specific proteases (Cryns and Yuan, 1999; Thornberry and Lazebnik, 1998). Caspases constitute a family of intracellular cysteine proteases (n= 11 in humans), which collaborate in proteolytic cascades where caspases activate themselves and each other. Within these proteolytic cascades, caspases can be positioned as either upstream “initiators” or downstream “effectors” of apoptosis. Several pathways for activating caspases exist (Figure 1). First, of the? 30 members of the tumor necrosis factor (TNF)-family receptors, eight contain a so-called death domain (DD) in their cytosolic tail (Locksley et al., 2001). Several of these DD-containing TNF-family receptors