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

Michela Puxeddu; Jianchao Wu; Ruoli Bai; Michele D'Ambrosio; Marianna Nalli; Antonio Coluccia; Simone Manetto; Alessia Ciogli; Domiziana Masci; Andrea Urbani; Cinzia Fionda; Sonia Coni; Rosa Bordone; Gianluca Canettieri; Chiara Bigogno; Giulio Dondio; Ernest Hamel; Te Liu; Romano Silvestri; Giuseppe La Regina

doi:10.1021/acs.jmedchem.2c01457

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

Michela Puxeddu
, Jianchao Wu
, Ruoli Bai
, Michele D'Ambrosio
, Marianna Nalli
, Antonio Coluccia
, Simone Manetto
, Alessia Ciogli
, Domiziana Masci
, Andrea Urbani
, Cinzia Fionda
, Sonia Coni
, Rosa Bordone
, Gianluca Canettieri
, Chiara Bigogno
, Giulio Dondio
, Ernest Hamel
, Te Liu^*
, Romano Silvestri^*
, Giuseppe La Regina^*

^*Corresponding author

University of Rome La Sapienza
Shanghai University of Traditional Chinese Medicine
National Institutes of Health
Sapienza University
Aphad SrL

Research output: Contribution to journal › Article

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 mu M. 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.

Original language	English
Pages (from-to)	15805-15818
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	65
DOIs	https://doi.org/10.1021/acs.jmedchem.2c01457
Publication status	Published - 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Anticancer agents
Ferroptosis
Glioblastoma
Ovarian Cancers
Pyrroles
Tubulin Assembly Inhibitors

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10.1021/acs.jmedchem.2c01457

Cite this

Puxeddu, M., Wu, J., Bai, R., D'Ambrosio, M., Nalli, M., Coluccia, A., Manetto, S., Ciogli, A., Masci, D., Urbani, A., Fionda, C., Coni, S., Bordone, R., Canettieri, G., Bigogno, C., Dondio, G., Hamel, E., Liu, T., Silvestri, R., & La Regina, G. (2022). Induction of Ferroptosis in Glioblastoma and Ovarian Cancers by a New Pyrrole Tubulin Assembly Inhibitor. Journal of Medicinal Chemistry, 65, 15805-15818. https://doi.org/10.1021/acs.jmedchem.2c01457

@article{fd56bfe1832d41a28228604af9a56c93,

title = "Induction of Ferroptosis in Glioblastoma and Ovarian Cancers by a New Pyrrole Tubulin Assembly Inhibitor",

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 mu M. 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.",

keywords = "Anticancer agents, Ferroptosis, Glioblastoma, Ovarian Cancers, Pyrroles, Tubulin Assembly Inhibitors, Anticancer agents, Ferroptosis, Glioblastoma, Ovarian Cancers, Pyrroles, Tubulin Assembly Inhibitors",

author = "Michela Puxeddu and Jianchao Wu and Ruoli Bai and Michele D'Ambrosio and Marianna Nalli and Antonio Coluccia and Simone Manetto and Alessia Ciogli and Domiziana Masci and Andrea Urbani and Cinzia Fionda and Sonia Coni and Rosa Bordone and Gianluca Canettieri and Chiara Bigogno and Giulio Dondio and Ernest Hamel and Te Liu and Romano Silvestri and \{La Regina\}, Giuseppe",

year = "2022",

doi = "10.1021/acs.jmedchem.2c01457",

language = "English",

volume = "65",

pages = "15805--15818",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

}

Puxeddu, M, Wu, J, Bai, R, D'Ambrosio, M, Nalli, M, Coluccia, A, Manetto, S, Ciogli, A, Masci, D , Urbani, A, Fionda, C, Coni, S, Bordone, R, Canettieri, G, Bigogno, C, Dondio, G, Hamel, E, Liu, T, Silvestri, R & La Regina, G 2022, 'Induction of Ferroptosis in Glioblastoma and Ovarian Cancers by a New Pyrrole Tubulin Assembly Inhibitor', Journal of Medicinal Chemistry, vol. 65, pp. 15805-15818. https://doi.org/10.1021/acs.jmedchem.2c01457

TY - JOUR

T1 - Induction of Ferroptosis in Glioblastoma and Ovarian Cancers by a New Pyrrole Tubulin Assembly Inhibitor

AU - Puxeddu, Michela

AU - Wu, Jianchao

AU - Bai, Ruoli

AU - D'Ambrosio, Michele

AU - Nalli, Marianna

AU - Coluccia, Antonio

AU - Manetto, Simone

AU - Ciogli, Alessia

AU - Masci, Domiziana

AU - Urbani, Andrea

AU - Fionda, Cinzia

AU - Coni, Sonia

AU - Bordone, Rosa

AU - Canettieri, Gianluca

AU - Bigogno, Chiara

AU - Dondio, Giulio

AU - Hamel, Ernest

AU - Liu, Te

AU - Silvestri, Romano

AU - La Regina, Giuseppe

PY - 2022

Y1 - 2022

N2 - 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 mu M. 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.

AB - 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 mu M. 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.

KW - Anticancer agents

KW - Ferroptosis

KW - Glioblastoma

KW - Ovarian Cancers

KW - Pyrroles

KW - Tubulin Assembly Inhibitors

KW - Anticancer agents

KW - Ferroptosis

KW - Glioblastoma

KW - Ovarian Cancers

KW - Pyrroles

KW - Tubulin Assembly Inhibitors

UR - http://hdl.handle.net/10807/267194

UR - https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.2c01457

U2 - 10.1021/acs.jmedchem.2c01457

DO - 10.1021/acs.jmedchem.2c01457

M3 - Article

SN - 0022-2623

VL - 65

SP - 15805

EP - 15818

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

ER -

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

Abstract

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Keywords

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