Verticillin A Causes Apoptosis and Reduces Tumor Burden in High-Grade Serous Ovarian Cancer by Inducing DNA Damage

Abstract

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 since most patients develop resistance to current frontline therapies. Many natural product and fungal metabolites exhibit anti-cancer activity and represent an untapped reservoir of potential new agents with unique mechanism(s) of action. Verticillin A, an epipolythiodioxopiperazine (ETP) alkaloid, is one such compound and our recent advances in fermentation and isolation are now enabling evaluation of its anti-cancer activity. Verticillin A demonstrated cytotoxicity in HGSOC cell lines in a dose-dependent manner with a low nM IC 50 . 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 *

Metabolites from Clonostachys Fungi and Their Biological Activities

“…Antinematodal activity [23] Bionectria sp. Y1085 - [17] Gliocladine C (39) Gliocladium roseum 1A Antinematodal activity [23] Gliocladine D (40) Gliocladium roseum 1A Antinematodal activity [23] Gliocladine E (41) Gliocladium roseum 1A Antinematodal activity [23] Glioclatine (42) Gliocladium roseum…”

“…Most of verticillins exhibited cytotoxic activities [ 11 , 27 ]. Among them, verticillin A ( 50 ) showed obviously cytotoxic acitivity by causing apoptosis and reducing tumor burden in high-grade serious ovarian cancer by inducing DNA damage [ 42 ]. Verticillins D ( 54 ) and G ( 55 ) were isolated from Bionectria byssicola , and verticillin G ( 55 ) was screened to have antibacterial activity on Staphylococcus aureus with MIC values of 3–10 μg/mL [ 25 ].…”

PHY34 inhibits autophagy through V-ATPase V0A2 subunit inhibition and CAS/CSE1L nuclear cargo trafficking in high grade serous ovarian cancer

“…For cell fractionation, nuclear and cytoplasmic protein fractions were isolated using NE-PER™ Nuclear and Cytoplasmic Extraction Reagents (Thermo Scientific™ #78833). Immunoblot analysis was performed as previously described [ 66 ]. Briefly, protein concentration was obtained using Bradford assay (Bio-Rad #5000205), and 20–30 μg protein per sample was separated by SDS-PAGE and transferred to nitrocellulose or activated 0.45 μm PVDF membranes (Thermo Fisher).…”

Cyclic Dipeptides: The Biological and Structural Landscape with Special Focus on the Anti-Cancer Proline-Based Scaffold

“…Verticillin A (131), Verticillin H (132), and their ester derivatives also exhibited strong cytotoxic effect on MDA-MB-231 and OVCAR3 cell lines (Table 6, entries [50][51], in the few cases, some of the ester derivatives showed higher cytotoxicity than the parent compounds [164]. Further studies proved the effectiveness of Verticillin A (131) in human gastric (AGS) [165], cervical (HeLa) [165], and ovarian cancer [166] cells lines (Table 6, entry 50). 11 -Deoxyverticillin (137) and 11,11 -dideoxyverticillin (138) were also very active against HCT-116 human colon carcinoma (IC 50 = 0.030 µM/mL) (Table 6, entries 56-57) [167] and 11,11 -dideoxyverticillin (138) also showed strong cytotoxic effect against human breast adenocarcinoma MDAMB-468, MCF-7, MDA-MB-435, and MDA-MB-231 cell lines with IC 50 values of 0.281, 0.158, 0.223, and 0.138 µM, respectively [168] (Table 6, entry 57).…”