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Chem. 2018 Oct 11;4(10):2370-2383. doi: 10.1016/j.chempr.2018.08.002 Q119.12024

Overcoming Drug Resistance by Targeting Cancer Bioenergetics with an Activatable Prodrug

通过激活前药靶向癌症生物能量学来克服药物抗性 翻译改进

Amit Sharma  1  2, Min-Goo Lee  3  2, Hu Shi  4  5  2, Miae Won  1, Jonathan F Arambula  6, Jonathan L Sessler  6  7, Jin Yong Lee  4, Sung-Gil Chi  3, Jong Seung Kim  1

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作者单位

  • 1 Department of Chemistry, Korea University, Seoul 02841 Korea.
  • 2 These authors contributed equally.
  • 3 Department of Life Sciences, Korea University, Seoul 02841, Korea.
  • 4 Department of Chemistry, Sungkyunkwan University, Suwon 16419, Korea.
  • 5 School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan, 030006, China.
  • 6 Department of Chemistry, University of Texas at Austin, Austin, TX 78712-1224, USA.
  • 7 Lead Contact.

    • DOI: 10.1016/j.chempr.2018.08.002 PMID: 39830500

    摘要 中英对照阅读

    Nearly without exception, all known cancer chemotherapeutics elicit a resistance response over time. The resulting resistance is correlated with poor clinical outcomes. Here, we report an approach to overcoming resistance through reprogramming oncogene-directed alterations in mitochondrial metabolism before drug activation while simultaneously circumventing drug efflux pumps. Conjugate C1 increases cancer cell apoptosis and inhibits regrowth of drug-resistant tumors, as inferred from efficacy studies carried out in human cancer cells and in Dox-resistant xenograft tumor models. It also displays minimal whole-animal toxicity. These benefits are ascribed to an ability to evade chemoresistance by switching cancer cell metabolism back to normal mitochondrial oxidative phosphorylation while helping target the active Dox to first the mitochondrion and then the nucleus.

    Keywords：drug resistance; cancer bioenergetics; activatable prodrug

    几乎无一例外，所有已知的癌症化疗药物都会随着时间的推移产生耐药性反应。由此产生的耐药性与不良的临床结果有关。在这里，我们报告了一种克服耐药性的方法，通过在药物激活前对线粒体代谢中癌基因导向的改变进行重新编程，同时绕过药物外排泵。缀合物C1增加癌症细胞凋亡并抑制耐药肿瘤的再生，这是从在人癌症细胞和Dox-resistant异种移植物肿瘤模型中进行的功效研究中推断的。它还显示出最小的全动物毒性。这些益处归因于通过将癌症细胞代谢切换回正常的线粒体氧化磷酸化来逃避化疗耐药性的能力，同时帮助活性Dox首先靶向线粒体，然后靶向细胞核。

    关键词：药物抵抗性; 癌症生物能量学; 可激活前药

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    期刊名：Chem

    缩写：CHEM-US

    ISSN：2451-9294

    e-ISSN：

    IF/分区：19.1/Q1

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