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Chemical-proteomics Identify Peroxiredoxin-1 as an Actionable Target in Triple-negative Breast Cancer

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 TNB...

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Published in:International journal of biological sciences 2023-01, Vol.19 (6), p.1731-1747
Main Authors: Spínola-Lasso, Elena, Montero, Juan Carlos, Jiménez-Monzón, Roberto, Estévez, Francisco, Quintana, José, Guerra, Borja, Elokely, Khaled M, León, Francisco, Del Rosario, Henoc, Fernández-Pérez, Leandro, López, Manuel Rodríguez, Díaz-Chico, Bonifacio Nicolás, McNaughton-Smith, Grant, Pandiella, Atanasio, Díaz-Chico, Juan Carlos
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Language:English
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Summary: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 and this combination was more effective than the individual treatments . 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 G /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
1449-2288
DOI:10.7150/ijbs.78554