B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. While overall survival rates are now over 80%, 15-20% of pediatric patients relapse, with survival 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 concentration (IC 50 ) of 3.2 μM and 3.3 μM, respectively. Cmpd10357, at a dose of 5mg/kg, significantly prolonged survival in our B-ALL xenograft mouse model, with a median survival time of 49.0 days compared to 45.5 days in the control group (p<0.05). The cytotoxicity of Cmpd10357 demonstrated caspase-independent, non-apoptotic cancer cell demise associated with the nuclear translocation of apoptosis-inducing factor (AIF). The cytotoxicity of Cmpd10357 in B-ALL cells was inhibited 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 of traditional apoptotic chemotherapeutic agents.
Keyphrases
- acute lymphoblastic leukemia
- cell death
- high grade
- cell cycle arrest
- free survival
- induced apoptosis
- endothelial cells
- childhood cancer
- mouse model
- endoplasmic reticulum stress
- oxidative stress
- allogeneic hematopoietic stem cell transplantation
- induced pluripotent stem cells
- single cell
- stem cells
- blood pressure
- acute myeloid leukemia
- cell proliferation