Systems biology of cisplatin resistance: past, present and future.
Systems biology of cisplatin resistance: past, present and future.
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DOI：
10.1038/cddis.2013.428
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发表时间：
2014-05-29
影响因子：
9
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中科院分区：
文献类型：
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铂衍生物顺式二氨二氯铂（II），最为人所知的是顺铂，目前用于睾丸癌、卵巢癌、头颈癌、结肠直肠癌、膀胱癌和肺癌患者的临床管理。长期以来，顺铂的抗肿瘤作用被完全归因于其产生不可修复的DNA损伤的能力，从而诱导称为细胞衰老的永久增殖停滞或凋亡的线粒体途径。越来越多的证据表明，顺铂的细胞抑制和细胞毒活性涉及细胞核和细胞质成分。尽管关于其作用机制的问题尚未解决，但顺铂的给药通常与高临床应答率相关。然而，在绝大多数情况下，暴露于顺铂的恶性细胞激活多管齐下的适应性反应，使它们对药物的抗增殖和细胞毒性作用不太敏感，并最终恢复增殖。因此，大部分顺铂治疗的患者注定会经历治疗失败和肿瘤复发。在过去的四十年里，人们一直致力于表征肿瘤细胞逐渐失去对顺铂敏感性的分子机制。高含量和高通量筛选技术的出现加速了细胞内源性和细胞外源性途径的发现，这些途径可以靶向预防或逆转癌症患者的顺铂耐药性。尽管如此，这种现象的多因素和冗余的性质对识别有效的化疗增敏策略构成了重大障碍。在这里，我们讨论了最近的系统生物学研究，旨在去卷积的复杂电路，支持顺铂耐药性，以及他们的研究结果可能会推动合理的方法来解决这个临床相关的问题的发展。
The platinum derivative cis-diamminedichloroplatinum(II), best known as cisplatin, is currently employed for the clinical management of patients affected by testicular, ovarian, head and neck, colorectal, bladder and lung cancers. For a long time, the antineoplastic effects of cisplatin have been fully ascribed to its ability to generate unrepairable DNA lesions, hence inducing either a permanent proliferative arrest known as cellular senescence or the mitochondrial pathway of apoptosis. Accumulating evidence now suggests that the cytostatic and cytotoxic activity of cisplatin involves both a nuclear and a cytoplasmic component. Despite the unresolved issues regarding its mechanism of action, the administration of cisplatin is generally associated with high rates of clinical responses. However, in the vast majority of cases, malignant cells exposed to cisplatin activate a multipronged adaptive response that renders them less susceptible to the antiproliferative and cytotoxic effects of the drug, and eventually resume proliferation. Thus, a large fraction of cisplatin-treated patients is destined to experience therapeutic failure and tumor recurrence. Throughout the last four decades great efforts have been devoted to the characterization of the molecular mechanisms whereby neoplastic cells progressively lose their sensitivity to cisplatin. The advent of high-content and high-throughput screening technologies has accelerated the discovery of cell-intrinsic and cell-extrinsic pathways that may be targeted to prevent or reverse cisplatin resistance in cancer patients. Still, the multifactorial and redundant nature of this phenomenon poses a significant barrier against the identification of effective chemosensitization strategies. Here, we discuss recent systems biology studies aimed at deconvoluting the complex circuitries that underpin cisplatin resistance, and how their findings might drive the development of rational approaches to tackle this clinically relevant problem.
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影响因子：
5.3
作者：
Chen, Helen H. W.;Yan, Jiang-Jou;Chen, Wen-Chung;Kuo, Macus Tien;Lai, Yu-Hsuan;Lai, Wu-Wei;Liu, Hsiao-Sheng;Su, Wu-Chou
通讯作者：
Su, Wu-Chou
影响因子：
6.4
作者：
Berndtsson, Maria;Hagg, Maria;Linder, Stig
通讯作者：
Linder, Stig
影响因子：
6.4
作者：
Brozovic, A;Fritz, G;Kaina, B
通讯作者：
Kaina, B
影响因子：
50.5
作者：
Bellmunt, J.;Paz-Ares, L.;Baselga, J.
通讯作者：
Baselga, J.
影响因子：
4.7
作者：
Barlin, Joyce N.;Jelinic, Petar;Levine, Douglas A.
通讯作者：
Levine, Douglas A.