1. Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Departamento de Bioquímica y Biología Molecular, Fisiología, Genética e Inmunología, Universidad de Las Palmas de Gran Canaria, The Canary Islands, Spain.
2. Institute of Biomedical Research of Salamanca (IBSAL), Instituto de Biología Molecular y Celular del Cáncer-CSIC and CIBERONC, Salamanca, Spain.
3. Instituto Canario de Investigación del Cáncer (ICIC), The Canary Islands, Spain.
4. Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Farmacología Molecular y Traslacional, Departamento de Ciencias Clínicas, Universidad de Las Palmas de Gran Canaria, The Canary Islands, Spain.
5. Unidad de Biomedicina asociada al CSIC, Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, The Canary Islands, Spain and Instituto de Investigaciones Biomédicas “Alberto Sols'' CSIC - Universidad Autónoma de Madrid, Madrid, Spain
6. Institute for Computational Molecular Science and Department of Chemistry, Temple University, Philadelphia, USA.
7. Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, USA.
8. Centro Atlántico del Medicamento S.A. (CEAMED S.A), La Laguna, The Canary Islands, Spain.
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.
Keywords: triple-negative breast cancer, quinone-fused oxazepine, peroxiredoxin-1, oxidative stress