TY - JOUR
T1 - Ferroptosis Induction by a New Pyrrole Derivative in Triple Negative Breast Cancer and Colorectal Cancer
AU - Masci, Domiziana
AU - Ling, Lele
AU - Yang, Lian
AU - Puxeddu, Michela
AU - Colla, Claudia
AU - Coluccia, Antonio
AU - Santelli, Martina
AU - Sciò, Pietro
AU - Cuřínová, Petra
AU - Ansari, Mohammad Salik Zeya
AU - Naro, Chiara
AU - Sette, Claudio
AU - Jimenez, Lucia
AU - Link, Wolfgang
AU - Bigogno, Chiara
AU - Dondio, Giulio
AU - Hamel, Ernest
AU - Liu, Te
AU - Silvestri, Romano
AU - Regina, Giuseppe La
PY - 2025
Y1 - 2025
N2 - 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 2-21. Compound 12 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 12 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 12 significantly lowered GSH, NADP+, and NADPH levels. Furthermore, lactoperoxidase, malondialdehyde, and Fe(II) levels significantly increased in 12-treated tissues, whereas superoxide dismutase concentrations decreased. Taken together, these results indicate that the antitumor activity of compound 12 was caused by the strong induction of ferroptosis. Given its high activity, compound 12 represents a promising therapeutic candidate for TNBC and CRC.
AB - 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 2-21. Compound 12 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 12 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 12 significantly lowered GSH, NADP+, and NADPH levels. Furthermore, lactoperoxidase, malondialdehyde, and Fe(II) levels significantly increased in 12-treated tissues, whereas superoxide dismutase concentrations decreased. Taken together, these results indicate that the antitumor activity of compound 12 was caused by the strong induction of ferroptosis. Given its high activity, compound 12 represents a promising therapeutic candidate for TNBC and CRC.
KW - Anticancer agents
KW - Colorectal Cancer
KW - Drug Design and Development
KW - Ferroptosis
KW - Pyrrole Derivatives
KW - Triple Negative Breast Cancer
KW - Anticancer agents
KW - Colorectal Cancer
KW - Drug Design and Development
KW - Ferroptosis
KW - Pyrrole Derivatives
KW - Triple Negative Breast Cancer
UR - https://publicatt.unicatt.it/handle/10807/321136
UR - https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=105014469330&origin=inward
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=105014469330&origin=inward
U2 - 10.1021/acs.jmedchem.5c01561
DO - 10.1021/acs.jmedchem.5c01561
M3 - Article
SN - 0022-2623
VL - 68
SP - 17840
EP - 17858
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 16
ER -
