Disulfide Cleavage in a Dimeric Epipolythiodioxopiperazine Natural Product Diminishes Its Apoptosis-Inducing Effect but Enhances Autophagy in Tumor Cells.,Journal of Natural Products

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Disulfide Cleavage in a Dimeric Epipolythiodioxopiperazine Natural Product Diminishes Its Apoptosis-Inducing Effect but Enhances Autophagy in Tumor Cells.
Journal of Natural Products ( IF 3.3 ) Pub Date : 2020-01-16 , DOI: 10.1021/acs.jnatprod.9b00994
Erwei Li ₁ , Bolin Hou ₁ , Quan Gao _{1,

2} , Yang Xu ₃ , Caining Zhang _{1,

2} , Xingzhong Liu ₁ , Xuejun Jiang ₁ , Yongsheng Che ₃

Affiliation

Gliocladicillin C (3) is a cytotoxic epipolythiodioxopiperazine (ETP) isolated from the Ophiocordyceps-associated fungus Clonostachys rogersoniana. Although the disulfides/polysulfides in ETPs are believed to account for their cytotoxicity, and 11'-deoxyverticillin A was demonstrated to induce apoptosis and autophagy, how they mediate apoptosis and autophagy remained unknown. Here, we revealed that 3 activated caspase-dependent apoptosis and autophagy in human tumor cells, while the prepared disulfide-cleavage product failed to induce reactive oxygen species production and PARP cleavage, but further enhanced the autophagic flux compared to 3. Gliocladicillin C and its derivative also increased the phosphorylation of AMP-activated protein kinase and stimulated autophagy by affecting the glycolytic pathway. These results demonstrated that the disulfides played an essential role in inducing apoptosis, but not autophagy.

中文翻译：

二聚体 Epipolythiodioxopiperazine 天然产物中的二硫化物裂解减弱了其诱导凋亡的作用，但增强了肿瘤细胞的自噬。

Gliocladicillin C (3) 是一种从 Ophiocordyceps 相关真菌 Clonostachys rogersoniana 中分离出来的细胞毒性表聚硫代二氧代哌嗪 (ETP)。尽管认为 ETP 中的二硫化物/多硫化物可以解释它们的细胞毒性，并且 11'-脱氧轮枝菌素 A 已被证明可诱导细胞凋亡和自噬，但它们如何介导细胞凋亡和自噬仍然未知。在这里，我们发现 3 在人肿瘤细胞中激活了半胱天冬酶依赖性细胞凋亡和自噬，而制备的二硫键裂解产物未能诱导活性氧产生和 PARP 裂解，但与 3 相比进一步增强了自噬通量。衍生物还增加了 AMP 活化蛋白激酶的磷酸化，并通过影响糖酵解途径刺激了自噬。

更新日期：2020-01-16

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