Therapeutic targeting of replicative immortality.
Therapeutic targeting of replicative immortality.
复制标题
复制永生的治疗靶向。
DOI：
10.1016/j.semcancer.2015.03.007
复制
发表时间：
2015-12
影响因子：
14.5
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
Yaswen P;MacKenzie KL;Keith WN;Hentosh P;Rodier F;Zhu J;Firestone GL;Matheu A;Carnero A;Bilsland A;Sundin T;Honoki K;Fujii H;Georgakilas AG;Amedei A;Amin A;Helferich B;Boosani CS;Guha G;Ciriolo MR;Chen S;Mohammed SI;Azmi AS;Bhakta D;Halicka D;Niccolai E;Aquilano K;Ashraf SS;Nowsheen S;Yang X
恶性细胞群体的特征之一是具有持续增殖的能力。这一特性允许克隆血统获得连续的像差，这些像差可以刺激日益自主的生长、侵袭性和治疗耐药性。与生俱来的细胞机制已经进化到调节复制潜力，以对冲恶性进展。当在没有正常的末端分化信号的情况下被激活时，这些机制可以导致持续的细胞停滞状态。这种状态被称为“衰老”，可以由内在的细胞过程触发，如端粒功能障碍和癌基因表达，也可由外部因素触发，如DNA损伤剂或氧化环境。尽管上游信号不同，衰老通常涉及肿瘤抑制基因p53和p16/pRb的相互依赖的趋同激活，但当这些抑制基因受损时，可以诱导衰老，尽管敏感性降低。实现癌细胞衰老所需的传统遗传毒性药物的剂量往往比实现细胞彻底死亡所需的剂量低得多。其他治疗方法，如针对细胞周期蛋白依赖性激酶或PI3K信号通路组件的治疗，可能通过绕过肿瘤抑制通路的缺陷或利用癌细胞对端粒酶的高要求来诱导癌细胞的衰老。这种足以诱导癌细胞衰老的治疗方法可以提供比传统细胞毒性疗法更少、更不严重的副作用，提高患者的存活率。这一积极的方面被关于衰老可逆性、基因组不稳定性和旁分泌效应的重要警告所抵消，这些效应可能增加存活癌细胞的异质性和适应性抵抗。然而，有效干扰复制不朽的药物很可能是癌症治疗新组合方法的有价值的组成部分。
One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed “senescence,” can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells’ heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy.
影响因子：
3.7
作者：
Ma Y;Yuan X;Wyatt WR;Pomerening JR
通讯作者：
Pomerening JR