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.