High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy in women worldwide and the fifth most common cause of cancer-related deaths among U.S. women. New therapies are needed to treat HGSOC, particularly because most patients develop resistance to current first-line therapies. Many natural product and fungal metabolites exhibit anticancer activity and represent an untapped reservoir of potential new agents with unique mechanism(s) of action. Verticillin A, an epipolythiodioxopiperazine alkaloid, is one such compound, and our recent advances in fermentation and isolation are now enabling evaluation of its anticancer activity. Verticillin A demonstrated cytotoxicity in HGSOC cell lines in a dose-dependent manner with a low nmol/L IC50. Furthermore, treatment with verticillin A induced DNA damage and caused apoptosis in HGSOC cell lines OVCAR4 and OVCAR8. RNA-Seq analysis of verticillin A–treated OVCAR8 cells revealed an enrichment of transcripts in the apoptosis signaling and the oxidative stress response pathways. Mass spectrometry histone profiling confirmed reports that verticillin A caused epigenetic modifications with global changes in histone methylation and acetylation marks. To facilitate in vivo delivery of verticillin A and to monitor its ability to reduce HGSOC tumor burden, verticillin A was encapsulated into an expansile nanoparticle (verticillin A-eNP) delivery system. In an in vivo human ovarian cancer xenograft model, verticillin A-eNPs decreased tumor growth and exhibited reduced liver toxicity compared with verticillin A administered alone. This study confirmed that verticillin A has therapeutic potential for treatment of HGSOC and that encapsulation into expansile nanoparticles reduced liver toxicity.

中文翻译：

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Verticillin A 通过诱导 DNA 损伤导致高级别浆液性卵巢癌的细胞凋亡并减少肿瘤负担

高级别浆液性卵巢癌 (HGSOC) 是全球女性最致命的妇科恶性肿瘤，也是美国女性癌症相关死亡的第五大常见原因。需要新疗法来治疗 HGSOC，特别是因为大多数患者对当前的一线疗法产生耐药性。许多天然产物和真菌代谢物表现出抗癌活性，代表了具有独特作用机制的潜在新药物的未开发库。轮枝菌素 A 是一种表聚硫代二氧代哌嗪生物碱，就是这样一种化合物，我们最近在发酵和分离方面的进展现在可以评估其抗癌活性。Verticillin A 在 HGSOC 细胞系中以剂量依赖性方式显示出细胞毒性，并且具有低 nmol/L IC50。此外，用轮枝菌素 A 处理在 HGSOC 细胞系 OVCAR4 和 OVCAR8 中诱导 DNA 损伤并导致细胞凋亡。轮枝菌素 A 处理的 OVCAR8 细胞的 RNA-Seq 分析揭示了细胞凋亡信号和氧化应激反应途径中转录物的富集。质谱组蛋白分析证实了轮枝菌素 A 导致表观遗传修饰，组蛋白甲基化和乙酰化标记发生整体变化的报道。为了促进轮枝菌素 A 的体内递送并监测其减少 HGSOC 肿瘤负荷的能力，轮枝菌素 A 被封装到可膨胀的纳米颗粒（轮枝菌素 A-eNP）递送系统中。在体内人卵巢癌异种移植模型中，与单独施用轮枝菌素 A 相比，轮枝菌素 A-eNPs 降低了肿瘤生长并表现出降低的肝毒性。