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.
Subject(s)
Triple Negative Breast Neoplasms , Humans , Apoptosis , Cell Line, Tumor , Cell Proliferation , Docetaxel/pharmacology , Molecular Docking Simulation , Proteomics , Triple Negative Breast Neoplasms/genetics , Xenograft Model Antitumor AssaysABSTRACT
INTRODUCTION AND OBJECTIVE: Spinal epidural hematoma (SEH) is an uncommon complication in hemophilic children. It can produce rapidly progressive neurological deficits. We aim to discuss the different management options for these patients. CASE REPORT: A 13-year-old boy with a history of hemophilia A was admitted with acute onset of localized spine pain and weakness. No trauma was reported on review of the history. Recombinant factor VIII aggressive replacement therapy was started. Spinal magnetic resonance imaging revealed an extradural mass lesion extending from D5 to D6 level. Emergency hemilaminectomies of D5 and D6 and evacuation of the clot were done. The patient made excellent recovery following surgery. CONCLUSION: Early diagnosis and immediate aggressive replacement therapy are mandatory in the management of SEH. Prompt surgical decompression to avoid any permanent neurological deficit is a safe and effective treatment option for an SEH in selected hemophilic children.
