A DNA Repair Inhibitor Isolated from an Ecuadorian Fungal Endophyte Exhibits Synthetic Lethality in PTEN-Deficient Glioblastoma.,Journal of Natural Products

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A DNA Repair Inhibitor Isolated from an Ecuadorian Fungal Endophyte Exhibits Synthetic Lethality in PTEN-Deficient Glioblastoma.
Journal of Natural Products ( IF 3.3 ) Pub Date : 2020-05-14 , DOI: 10.1021/acs.jnatprod.0c00012
Nneoma Adaku ₁ , Hyun Bong Park _{2,

3} , Daniel J Spakowicz ₄ , Meetu Kaushik Tiwari ₁ , Scott A Strobel _{3,

4} , Jason M Crawford _{2,

3,

5} , Faye A Rogers _{1,

6}

Affiliation

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 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.

中文翻译：

从厄瓜多尔真菌内生菌中分离的 DNA 修复抑制剂在 PTEN 缺陷型胶质母细胞瘤中表现出合成致死性。

在蛋白质或基因组水平上破坏肿瘤抑制因子 PTEN，在人类癌症发展中起着重要作用。在几种癌症亚型中报告的高频率 PTEN 缺陷使利用 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。在这里，我们报告从药用植物中分离出的内生真菌产生 DNA 双链断裂修复抑制剂。此外，我们命名为irrepairzepine的新型生物碱产品（1)，在 PTEN 缺陷的胶质母细胞瘤细胞中证明了合成致死靶向。我们的研究结果揭示了 PTEN 缺陷癌症的新治疗先导，以及提高当前癌症治疗功效的重要分子工具。

更新日期：2020-06-26

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