Cmpd10357 to treat B-cell acute lymphoblastic leukemia
Autor: | Alex Q. Lee, Hiroaki Konishi, Elizabeth Helmke, Masami Ijiri, Jan Michael A. Lerot, Emma Hicks, Jeremy R. Chien, Fredric A. Gorin, Noriko Satake |
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Rok vydání: | 2023 |
Předmět: |
Pediatric
Pediatric Research Initiative Cancer Research Tumor Childhood Leukemia Pediatric Cancer Immunology Antineoplastic Agents Apoptosis Cell Biology Hematology Cardiorespiratory Medicine and Haematology Burkitt Lymphoma Cell Line Mice Rare Diseases Orphan Drug Caspases Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Genetics Animals Humans Child Molecular Biology Cancer |
Zdroj: | Experimental Hematology. :8-13.e1 |
ISSN: | 0301-472X |
Popis: | B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of cancer found in children. Although the overall survival rates are now >80%, 15%-20% of pediatric patients relapse, with survival rates subsequently dropping to 5%-10%. Cmpd10357, 3-amino-5-arylamino-6-chloro-N- (diaminomethylene) pyrazine-2-carboximide, is a highly potent, cell-permeant compound recently shown to have cytotoxic effects on solid tumors, including human breast cancer and high-grade gliomas, independent of their proliferative status. Cmpd10357 demonstrated concentration-dependent cytotoxicity in two human B-ALL cell lines, JM1 and Reh, at half-maximal inhibitory concentrations (IC50) of 3.2 and 3.3 μM, respectively. Cmpd10357, at a dose of 5 mg/kg, significantly prolonged survival in our B-ALL xenograft mouse model, with a median survival time of 49.0 days compared with 45.5 days in the control group (p < 0.05). The cytotoxicity of Cmpd10357 demonstrated caspase-independent, nonapoptotic cancer cell demise associated with the nuclear translocation of apoptosis-inducing factor (AIF). The cytotoxicity of Cmpd10357 in B-ALL cells was inhibited by Necrostatin-1 but not by Necrosulfonamide. These studies suggest that an AIF-mediated, caspase-independent necrosis mechanism of Cmpd10357 in B-ALL could be used in combination with traditional apoptotic chemotherapeutic agents. |
Databáze: | OpenAIRE |
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