Chicago Biomedical Consortium, Northwestern University, Evanston, Illinois 60208, United States.
Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60607, United States.
J Nat Prod. 2023 Sep 22;86(9):2102-2110. doi: 10.1021/acs.jnatprod.3c00186. Epub 2023 Aug 29.
High-grade serous ovarian cancer (HGSOC) is the most common and lethal ovarian cancer histotype. Lack of early detection methods, limited therapeutic agents, and low 5-year survival rate reflect the urgent need to develop new therapies. Eupenifeldin, a bistropolone, originally isolated from , is a cytotoxic fungal metabolite. In three HSGOC cell lines (OVCAR3, OVCAR5, OVCAR8), eupenifeldin was found to have an IC value less than 10 nM, while 10 times higher concentrations were required for cytotoxicity in nontumorigenic fallopian tube secretory epithelial cell lines (FTSEC). An in vivo hollow fiber assay showed significant cytotoxicity in OVCAR3. Eupenifeldin significantly increased Annexin V staining in OVCAR3 and -8, but not OVCAR5. Eupenifeldin activated caspases 3/7 in OVCAR3, OVCAR5, and OVCAR8; however, cleaved PARP was only detected in OVCAR3. Quantitative proteomics performed on OVCAR3 implicated ferroptosis as the most enriched cell death pathway. However, validation experiments did not support ferroptosis as part of the cytotoxic mechanism of eupenifeldin. Autophagic flux and LC3B puncta assays found that eupenifeldin displayed weak autophagic induction in OVCAR3. Inhibition of autophagy by cotreatment with bafilomycin reduced the toxicity of eupenifeldin, supporting the idea that induction of autophagy contributes to the cytotoxic mechanism of eupenifeldin.
高级别浆液性卵巢癌（HGSOC）是最常见和致命的卵巢癌组织类型。缺乏早期检测方法、有限的治疗药物和低 5 年生存率反映了迫切需要开发新的治疗方法。Eupenifeldin 是一种双稠吡咯烷，最初从 中分离出来，是一种细胞毒性真菌代谢物。在三种 HSGOC 细胞系（OVCAR3、OVCAR5、OVCAR8）中，发现 eupenifeldin 的 IC 值小于 10 nM，而在非肿瘤性输卵管分泌上皮细胞系（FTSEC）中则需要 10 倍以上的浓度才能产生细胞毒性。体内空心纤维测定显示，eupenifeldin 在 OVCAR3 中具有显著的细胞毒性。Eupenifeldin 显著增加了 OVCAR3 和 -8 中的 Annexin V 染色，但对 OVCAR5 则没有。Eupenifeldin 在 OVCAR3、OVCAR5 和 OVCAR8 中激活了 caspase 3/7；然而，只有在 OVCAR3 中检测到裂解的 PARP。对 OVCAR3 进行的定量蛋白质组学研究表明，铁死亡是最丰富的细胞死亡途径。然而，验证实验并不支持铁死亡是 eupenifeldin 细胞毒性机制的一部分。自噬通量和 LC3B 斑点测定发现，eupenifeldin 在 OVCAR3 中显示出较弱的自噬诱导。用 bafilomycin 共同处理抑制自噬，降低了 eupenifeldin 的毒性，支持了自噬诱导有助于 eupenifeldin 细胞毒性机制的观点。
