RT Journal Article SR Electronic T1 Verticillin A Causes Apoptosis and Reduces Tumor Burden in High-Grade Serous Ovarian Cancer by Inducing DNA Damage JF Molecular Cancer Therapeutics JO Mol Cancer Ther FD American Association for Cancer Research SP 89 OP 100 DO 10.1158/1535-7163.MCT-19-0205 VO 19 IS 1 A1 Salvi, Amrita A1 Amrine, Chiraz Soumia M. A1 Austin, Julia R. A1 Kilpatrick, KiAundra A1 Russo, Angela A1 Lantvit, Daniel A1 Calderon-Gierszal, Esther A1 Mattes, Zachary A1 Pearce, Cedric J. A1 Grinstaff, Mark W. A1 Colby, Aaron H. A1 Oberlies, Nicholas H. A1 Burdette, Joanna E. YR 2020 UL http://mct.aacrjournals.org/content/19/1/89.abstract AB 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.