Background
C188-9 is a STAT3 inhibitor.1,2 It binds to the phosphotyrosyl peptide binding site in the STAT3 Src homology 2 (SH2) domain (Ki = 136 nM) and inhibits G-CSF-induced activation of STAT3 in patient-derived acute myeloid leukemia (AML) cells (IC50s = 8-18 ?M). C188-9 induces apoptosis in patient-derived AML cells (EC50s = 6-50 ?M) and reduces viability of HepG2, Huh7, and PLC/PRF/5 hepatoma cells (IC50s = 10.19, 11.27, and 11.83 ?M, respectively).2,3 In vivo, C188-9 (100 mg/kg) reduces hepatic Pten deletion-induced hepatic macro- and microsteatosis, which reduces the development of hepatocellular carcinomas in mice. C188-9 (12.5 mg/kg) increases muscle fiber size in a murine Lewis lung carcinoma model of cancer cachexia.1
1.Silva, K.A.S., Dong, J., Dong, Y., et al.Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexiaJ. Biol. Chem.290(17)11177-11187(2015)
2.Redell, M.S., Ruiz, M.J., Alonzo, T.A., et al.Stat3 signaling in acute myeloid leukemia: Ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitorBlood117(21)5701-5709(2011)
3.Jung, K.H., Yoo, W., Stevenson, H.L., et al.Multifunctional effects of a small-molecule STAT3 inhibitor on NASH and hepatocellular carcinoma in miceClin. Cancer Res.23(18)5537-5546(2017)
Protocol
Cell experiment: | Cell lines are plated at 2 to 5×105 cells/mL in growth medium and treated with increasing doses of inhibitor for 24 hours. CD34+ AML cells are plated at 1 to 2×105 cells/mL in IMDM with 20% FBS and Pen/Strep, and incubated with C188-9 (0.3 to 100 μM) for 48 hours. Cells are then harvested and labeled. The fraction of spontaneous apoptosis is determined from an untreated sample and then subtracted from the drug-treated samples to yield the percentage of apoptosis attributed to drug treatment[1]. |
Animal experiment: | Mice[3]UM-SCC-17B cells (1.5×106) are injected into the tongues of athymic, 8-10 week old, male, nude mice. Once tumors are established, mice (20 total; 10/group) are randomized (average tumor vol ~15-20 mm3) to receive 5 times a week, intraperitoneal injections of either DMSO or C188 (50 mg/kg) or C188-9 (100 mg/kg). Tumor volumes are measured twice weekly. Average tumor volumes 6/πx (long dimension) x (short dimension)2)) are calculated and normalized to the volume at first day of treatment and plotted comparison is done by t test (* p<0.05) [3]. |
参考文献: [1]. Silva KA, et al. Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexia. J Biol Chem. 2015 Apr 24;290(17):11177-87.
[2]. Redell MS, et al. Stat3 signaling in acute myeloid leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood. 2011 May 26;117(21):5701-9.
[3]. Bharadwaj U, et al. Small-molecule inhibition of STAT3 in radioresistant head and neck squamous cell carcinoma. Oncotarget. 2016 May 3;7(18):26307-30. |
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