Induction of Ferroptosis in Glioblastoma and Ovarian Cancers by a New Pyrrole Tubulin Assembly Inhibitor

We synthesized new
aroyl diheterocyclic pyrrole (ARDHEP) 15 that exhibited
the hallmarks of ferroptosis. Compound 15 strongly inhibited
U-87 MG, OVCAR-3, and MCF-7 cancer cells,
induced an increase of cleaved PARP, but was not toxic for normal
human primary T lymphocytes at 0.1 μM. Analysis of the levels
of lactoperoxidase, malondialdehyde, lactic acid, total glutathione,
and ATP suggested that the in vivo inhibition of cancer cell proliferation
by 15 went through stimulation of oxidative stress injury
and Fe2+ accumulation. Quantitative polymerase chain reaction
analysis of the mRNA expression in U-87 MG and SKOV-3 tumor tissues
from 15-treated mice showed the presence of Ptgs2/Nfe2l2/Sat1/Akr1c1/Gpx4 genes correlated with ferroptosis in both
groups. Immunofluorescence staining revealed significantly lower expressions
of proteins Ki67, CD31, and ferroptosis negative regulation proteins
glutathione peroxidase 4 (GPX4) and FTH1. Compound 15 was found to be metabolically stable when incubated with human liver
microsomes.