Background
HJC0152 is an orally bioavailable inhibitor of STAT3 (32 and 62% inhibition at 10 and 20 ?M, respectively, in MDA-MB-231 cells in a luciferase reporter assay).1 It reduces total STAT3 and phosphorylated STAT3 levels in MDA-MB-231 cells and inhibits nuclear translocation of phosphorylated STAT3. HJC0152 inhibits proliferation of MCF-7 and MDA-MB-231 breast cancer and AsPC-1 and PANC-1 pancreatic cancer cells (IC50s = 0.91, 1.64, 1.9, and 1.08 ?M, respectively). It also halts the cell cycle at the G0/G1 phase, induces apoptosis, and suppresses cell proliferation in human head and neck squamous cell carcinoma cells.2 HJC0152 (7.5 mg/kg, i.p. or 25 mg/kg, p.o.) inhibits tumor growth in an MDA-MB-231 breast cancer mouse xenograft model and in an orthotopic mouse model of squamous cell carcinoma.1,2
1.Chen, H., Yang, Z., Ding, C., et al.Discovery of O-alkylamino tethered niclosamide derivatives as potent and orally bioavailable anticancer agentsACS Med. Chem. Lett.4(2)180-185(2013)
2.Wang, Y., Wang, S., Wu, Y., et al.Suppression of the growth and invasion of human head and neck squamous cell carcinomas via regulating STAT3 signaling and the miR-21/β-catenin axis with HJC0152Mol. Cancer Ther.16(4)578-590(2017)
Protocol
Cell experiment: | Breast cancer MDA-MB-231 cells are incubated in 6-well plates (2.5×105/well). Cells are then treated with DMSO, or HJC0152 hydrochloride (compound 11) at different concentrations for 48 h, and then both adherent and floating cells are collected, washed once with PBS. Resuspended cells are incubated with 100 μL PBS containing 1% BSA and 100 μL Annexin V and dead cell detection reagent at room temperature for 20 min. Apoptosis is measured immediately using the Muse Cell Analyzer with the MuseTM Apoptosis Kit[1]. |
Animal experiment: | in vivo administration.--> Fifty-four female nude mice are are used for orthotopic tumor studies at 4 to 6 weeks of age. The mice are maintained in a barrier unit with 12 h light-dark switch. Freshly harvested MDA-MB-231 cells (2.5×106 cells per mouse, resuspended in 100 μL PBS) are injected into the 3rd mammary fat pad of the mice, and then randomly assigned into 8 groups (5 to10 mice per group). For the intraperitoneal treatment experiment, the mice are treated daily with 2.5 mg/kg HJC0152 hydrochloride (compound 11) (Group A) or vehicle (Group D) when the tumor volume reaches 200 mm3. A Body weights and tumors volume are measured daily and tumor volume is calculated according to the formula V=0.5×L×W2, where L=length (mm) and W=width (mm)[1]. |
参考文献: [1]. Chen H, et al. Discovery of O-Alkylamino Tethered Niclosamide Derivatives as Potent and Orally Bioavailable Anticancer Agents. ACS Med Chem Lett. 2013 Feb 14;4(2):180-185. |
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