2. Academic Validation
  3. Induction of Ferroptosis in Glioblastoma and Ovarian Cancers by a New Pyrrole Tubulin Assembly Inhibitor

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

  • J Med Chem. 2022 Nov 17. doi: 10.1021/acs.jmedchem.2c01457.
Michela Puxeddu 1,  Jianchao Wu 2,  Ruoli Bai 3,  Michele D'Ambrosio 1,  Marianna Nalli 1,  Antonio Coluccia 1,  Simone Manetto 1,  Alessia Ciogli 1,  Domiziana Masci 4,  Andrea Urbani 4,  Cinzia Fionda 5,  Sonia Coni 5,  Rosa Bordone 5,  Gianluca Canettieri 5,  Chiara Bigogno 6,  Giulio Dondio 6,  Ernest Hamel 3,  Te Liu 2,  Romano Silvestri 1,  Giuseppe La Regina 1
Affiliations

Affiliations

  • 1 Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185Rome, Italy.
  • 2 Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 365 South Xiangyang Road, 200031Shanghai, China.
  • 3 Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland21702, United States.
  • 4 Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168Rome, Italy.
  • 5 Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161Rome, Italy.
  • 6 Aphad SrL, Via della Resistenza 65, 20090Buccinasco, Italy.
PMID: 36395526 DOI: 10.1021/acs.jmedchem.2c01457
Abstract

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.

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