A DNA Repair Inhibitor Isolated from an Ecuadorian Fungal Endophyte Exhibits Synthetic Lethality in PTEN-Deficient Glioblastoma.
A DNA Repair Inhibitor Isolated from an Ecuadorian Fungal Endophyte Exhibits Synthetic Lethality in PTEN-Deficient Glioblastoma.
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从厄瓜多尔真菌内生菌中分离出的 DNA 修复抑制剂在 PTEN 缺陷的胶质母细胞瘤中表现出合成致死性。
DOI：
10.1021/acs.jnatprod.0c00012
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发表时间：
2020-05
影响因子：
5.1
通讯作者：
Nneoma Adaku;Hyun Bong Park;Daniel J Spakowicz;M. Tiwari;S. Strobel;J. Crawford;F. Rogers
中科院分区：
文献类型：
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作者：
Nneoma Adaku;Hyun Bong Park;Daniel J Spakowicz;M. Tiwari;S. Strobel;J. Crawford;F. Rogers
肿瘤抑制因子 PTEN 的破坏，无论是在蛋白质水平还是基因组水平，在人类癌症的发展中都起着重要作用。在几种癌症亚型中报告的 PTEN 缺乏频率很高，这使得利用 PTEN 功能丧失的治疗方法能够显着影响大量患者群体的治疗策略。在此，我们报告从亚马逊土著居民使用的药用植物中分离出的内生真菌可产生 DNA 双链断裂修复抑制剂。此外，我们将这种新型生物碱产品命名为 irrepairzepine (1)，它在 PTEN 缺陷的胶质母细胞瘤细胞中表现出合成致死靶向作用。我们的研究结果揭示了 PTEN 缺陷癌症的新治疗先导，也是增强当前癌症治疗功效的重要分子工具。
Disruption of the tumor suppressor PTEN, either at the protein or genomic level, plays an important role in human cancer development. The high frequency of PTEN deficiency reported across several cancer subtypes positions therapeutic approaches that exploit PTEN loss-of-function with the ability to significantly impact the treatment strategies of a large patient population. Here, we report that an endophytic fungus isolated from a medicinal plant used by Indigenous Amazonians produces an inhibitor of DNA double-strand-break repair. Furthermore, the novel alkaloid product, which we have named irrepairzepine (1), demonstrated synthetic lethal targeting in PTEN-deficient glioblastoma cells. Our results uncover a new therapeutic lead for PTEN-deficient cancers and an important molecular tool toward enhancing the efficacy of current cancer treatments.