| In Vivo | AVN-944 (0-150 mg/kg, Orally, twice daily) significantly increases the median survival time of leukemia model mice. Animal model: Balb/c mice (leukemia model, using Ba/F3 cells transduced with an activating human Flt-3 mutation injected into mice). Dosage: 75 or 150 mg/kg. Administration: Orally, twice daily. Result: Provided a significant increase in median survival time. Three of the 12 mice treated with 150 mg/kg AVN-944 were still alive on Day 35 when the study was terminated. |
|---|
| In Vitro | AVN-944 (0-1 μM, 48 h) inhibits growth of human multiple myeloma (MM) cell lines in a dose-dependent manner. AVN-944 (800 nM, 0-72 h) induces apoptosis in MM cell lines via a caspase-independent, Bax/AIF/Endo G pathway. AVN-944 (0-200 nM) enhances the cytotoxicity of Doxorubicin (HY-15142A) and Melphalan (HY-17575). AVN-944 inhibits the proliferation of the human MV-4-11 and murine Ba/F3-Flt3-ITD-dependent cell lines with IC50 values of 26 and 30 nM, respectively. AVN-944 (0-32 μM, 48 h) shows good activity against arenavirus infection at low doses (7.5 μM) with less cytotoxicity. AVN-944 (0-6.4 μM, 48 h) does not reduce the viability of peripheral blood mononuclear cells (PBMNCs). Cell Proliferation Assay Cell line: RPMI8226, MM.1S, and U266 cells Concentration: 0, 100, 200, 300, 400, 600, 1000 nM. Incubation time: 48 h. Result: Significantly inhibited the growth of RPMI8226, MM.1S, and U266 cells in a dose-dependent fashion, with 50% inhibition (IC50) values at 48 h of 450, 450, and 600 nM, respectively. Inhibited growth of drug-resistant cell lines, including Doxorubicin (Dox)-resistant RPMI8226-Dox40, Melphalan (Mel) resistant RPMI8226-LR5, and Dex (Dexamethasone) resistant MM.1R cells, with IC50 values similar to the parental drug-sensitive cell lines. Apoptosis Analysis Cell line: MM.1S and RPMI8226 cells Concentration: 800 nM. Incubation time: 48 and 72 h. Result: Induced apoptosis in MM cell lines. Western blot analysis. Cell line: MM.1S and RPMI8226 cells Concentration: 800 nM. Incubation time: 12, 24, 48 h. Result: Induced modest cleavage of caspase 3, 8 and 9 in MM.1S cells and RPMI8226 cells. Markedly upregulated Bax and Bak, without significant changes in Bcl-2, Mcl-1, XIAP, and Bad. Observed translocation of mitochondrial proapoptotic proteins, apoptosis-inducing factor (AIF) and endonuclease G (Endo G) to cytosolic fractions. Cell Cytotoxicity Assay Cell line: MM.1S cells, MM.1S cells cultured with BMSCs Concentration: 0, 50, 200 nM. Incubation time: 24 h. Result: Enhanced the cytotoxicity of of Doxorubicin and Melphalan in MM.1S cells. Additive effects were also observed in MM.1S cells cultured with BMSCs derived from MM patient. |
|---|
