Targeting the DNA damage response (DDR) by natural compounds.,Bioorganic & Medicinal Chemistry

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Targeting the DNA damage response (DDR) by natural compounds.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2020-01-08 , DOI: 10.1016/j.bmc.2019.115279
Jana van Stuijvenberg ₁ , Peter Proksch ₂ , Gerhard Fritz ₁

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Natural compounds (NC) are an important source of anticancer drugs. The genomic DNA of tumor cells is a major target of conventional anticancer therapeutics (cAT). DNA damage elicits a complex stress response programme termed DNA damage response (DDR), with the PI3-like kinase ATM and ATR being the key regulators. Since the DDR coordinates mechanisms of DNA repair and apoptosis, hence regulating the balance between death and survival, it is an attractive target of novel anticancer strategies. The aim of the study was to identify natural compounds derived from endophytic fungi, lichens, marine sponges or plants that interfere with mechanisms of the DDR. To this end, the cytotoxic and DDR modulating potency of 296 natural compounds, used alone or in combination with the cAT cisplatin (Cis) and doxorubicin (Doxo) was investigated by fluorescence-based analysis of the ATM/ATR-catalyzed S139 phosphorylation of histone 2AX (γH2AX), a surrogate marker of DNA damage-triggered DDR. After initial screening, a total of ten natural compounds were identified that were toxic in pancreatic carcinoma cells and activated the DDR on their own and/or promoted the DDR if used in combination with cAT. Their mode of action was shown to be independent of drug transport mechanisms. Based on their chemical structures, DDR modulatory activity and published data we suggest the marine NC 5-epi-nakijiquinone Q and 5-epi-ilimaquinone as well as the fungal compound secalonic acid F as most promising NC-based drug candidates for future synthesis of DDR-modulating chemical derivatives and their preclinical in vitro and in vivo testing.

中文翻译：

通过天然化合物靶向DNA损伤反应（DDR）。

天然化合物（NC）是抗癌药物的重要来源。肿瘤细胞的基因组DNA是常规抗癌疗法（cAT）的主要目标。DNA损伤引发了一个复杂的应激反应程序，称为DNA损伤反应（DDR），PI3样激酶ATM和ATR是关键调节因子。由于DDR协调DNA修复和凋亡的机制，从而调节死亡和存活之间的平衡，因此它是新型抗癌策略的引人注目的目标。该研究的目的是鉴定源自内生真菌，地衣，海洋海绵或植物的天然化合物，它们会干扰DDR的机制。为此，296种天然化合物具有细胞毒性和DDR调节能力，通过对ATM / ATR催化的组蛋白2AX（γH2AX）的S139磷酸化进行基于荧光的分析，研究了单独使用或与cAT顺铂（Cis）和阿霉素（Doxo）结合使用的DNA损伤触发DDR的替代标记。初步筛选后，鉴定出总共十种对胰腺癌细胞有毒的天然化合物，如果与cAT组合使用，它们会自行激活DDR和/或促进DDR。已证明它们的作用方式独立于药物转运机制。根据它们的化学结构，

更新日期：2020-01-09

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