Ferroptosis Induction by a New Pyrrole Derivative in Triple Negative Breast Cancer and Colorectal Cancer
Ferroptosis-inducing agents are an emerging class of nonapoptotic, iron-dependent compounds for anticancer chemotherapy. We describe the synthesis of new aroyl diheterocyclyl pyrrole derivatives <b>2-21</b>. Compound <b>12</b> exhibited the most potent in vitro anticancer activity against breast cancer (BC), triple-negative breast cancer (TNBC), and colorectal cancer (CRC) cell lines, as well as significant efficacy in an HCT116 CRC xenograft model. Compound <b>12</b> showed typical hallmarks of ferroptosis in HCT116 cells from tumor tissues both in immunofluorescence and a qPCR gene assay and in the expression of ferroptosis inhibited proteins. Compound <b>12</b> significantly lowered GSH, NADP<sup>+</sup>, and NADPH levels. Furthermore, lactoperoxidase, malondialdehyde, and Fe(II) levels significantly increased in <b>12</b>-treated tissues, whereas superoxide dismutase concentrations decreased. Taken together, these results indicate that the antitumor activity of compound <b>12</b> was caused by the strong induction of ferroptosis. Given its high activity, compound <b>12</b> represents a promising therapeutic candidate for TNBC and CRC.
Authors
- Mohammad Salik Zeya Ansari (ORCID: https://orcid.org/0000-0002-9938-8142)
- Domiziana Masci (ORCID: https://orcid.org/0000-0002-5615-5111)
- Chiara Bigogno
- Wolfgang Link (ORCID: https://orcid.org/0000-0002-3340-5165)
- Claudio Sette (ORCID: https://orcid.org/0000-0003-2864-8266)
- Lian Yang (ORCID: https://orcid.org/0000-0002-0646-5971)
- Petra Cuřínová (ORCID: https://orcid.org/0000-0001-8264-7032)
- Chiara Naro (ORCID: https://orcid.org/0000-0002-3135-3218)
- Lele Ling (ORCID: https://orcid.org/0000-0002-6782-4181)
- Maurice Santelli (ORCID: https://orcid.org/0000-0002-0033-0072)
- Romano Silvestri (ORCID: https://orcid.org/0000-0003-2489-0178)
- Antonio Coluccia (ORCID: https://orcid.org/0000-0002-7940-8206)
- Lucía Jiménez (ORCID: https://orcid.org/0000-0001-9576-1766)
- Giuseppe La Regina (ORCID: https://orcid.org/0000-0003-3252-1161)
- Michela Puxeddu (ORCID: https://orcid.org/0000-0002-0024-596X)
- Ernest Hamel (ORCID: https://orcid.org/0000-0003-3648-103X)
- Giulio Dondio (ORCID: https://orcid.org/0000-0001-5023-3804)
- Pietro Sciò
- Te Liu
- Claudia Colla
Institutions
- Università Cattolica del Sacro Cuore (IT)
- National Institutes of Health (US)
- Global Environment Facility (US)
- Shanghai Jiao Tong University (CN)
- Agostino Gemelli University Polyclinic (IT)
- Shanghai University of Traditional Chinese Medicine (CN)
- Frederick National Laboratory for Cancer Research (US)
- National Research Council (LK)
- Shanghai First People's Hospital (CN)
- National Cancer Institute (US)
- China Association of Acupuncture-Moxibustion (CN)
- Istituto Pasteur (IT)
- Universidad Autónoma de Madrid (ES)
- University of Chemistry and Technology, Prague (CZ)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-11
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01561
- Citations
- 1
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- Ministero della Salute
- Sapienza Università di Roma
- Associazione Italiana per la Ricerca sul Cancro
- Università Cattolica del Sacro Cuore
- State Administration of Traditional Chinese Medicine of the People's Republic of China
- Ministero dell'Università e della Ricerca
- European Regional Development Fund
- Agencia Estatal de Investigación