Cmpd10357 to treat B-cell acute lymphoblastic leukemia.
Exp Hematol
; 119-120: 8-13.e1, 2023.
Article
en En
| MEDLINE
| ID: mdl-36621746
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
2_ODS3
/
6_ODS3_enfermedades_notrasmisibles
/
7_ODS3_muertes_prevenibles_nacidos_ninos
Problema de salud:
2_muertes_prevenibles
/
6_leukemia
/
6_lymphomas_multiple_myeloma
/
7_non_communicable_diseases
Asunto principal:
Leucemia-Linfoma Linfoblástico de Células Precursoras B
/
Linfoma de Burkitt
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Child
/
Humans
Idioma:
En
Revista:
Exp Hematol
Año:
2023
Tipo del documento:
Article
País de afiliación:
Canadá