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Title: Chemical-proteomics Identify Peroxiredoxin-1 as an Actionable Target in Triple-negative Breast Cancer
Authors: Spinola Lasso, Elena 
Montero, Juan Carlos
Jiménez Monzón,Roberto 
Estévez Rosas, Francisco Jesús 
Quintana Aguiar, José Martín 
Guerra Hernández, Carlos Borja 
Elokely, Khaled M.
León, Francisco
Del Rosario García, Henoc 
Fernández Pérez, Leandro Fco 
Rodríguez López, Manuel
Díaz Chico, Bonifacio 
McNaughton-Smith, Grant
Pandiella Alonso,Atanasio 
Díaz Chico, Juan Carlos 
UNESCO Clasification: 32 Ciencias médicas
320101 Oncología
2407 Biología celular
Keywords: Triple-negative breast cancer
Quinone-fused oxazepine
Oxidative stress
Issue Date: 2023
Journal: International Journal of Biological Sciences 
Abstract: Triple-negative breast cancer (TNBC) is difficult to treat; therefore, the development of drugs directed against its oncogenic vulnerabilities is a desirable goal. Herein, we report the antitumor effects of CM728, a novel quinone-fused oxazepine, against this malignancy. CM728 potently inhibited TNBC cell viability and decreased the growth of MDA-MB-231-induced orthotopic tumors. Furthermore, CM728 exerted a strong synergistic antiproliferative effect with docetaxel in vitro and this combination was more effective than the individual treatments in vivo. Chemical proteomic approaches revealed that CM728 bound to peroxiredoxin-1 (Prdx1), thereby inducing its oxidation. Molecular docking corroborated these findings. CM728 induced oxidative stress and a multi-signal response, including JNK/p38 MAPK activation and STAT3 inhibition. Interestingly, Prdx1 downregulation mimicked these effects. Finally, CM728 led to DNA damage, cell cycle blockage at the S and G2/M phases, and the activation of caspase-dependent apoptosis. Taken together, our results identify a novel compound with antitumoral properties against TNBC. In addition, we describe the mechanism of action of this drug and provide a rationale for the use of Prdx1 inhibitors, such as CM728, alone or in combination with other drugs, for the treatment of TNBC.
ISSN: 1449-2288
DOI: 10.7150/ijbs.78554
Source: International Journal of Biological Sciences [1449-2288], v. 19(6), pp. 1731-1747 (Marzo 2023)
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