Abstract: Objective To investigate the effects of fritinib on angiogenesis, tumor growth and inositol requiring enzyme 1 （IRE1）-apoptosis signal regulating kinase 1 （ASK1）-c-Jun N-terminal kinase （JNK） pathway in triple negative breast cancer. Methods Triple negative breast cancer cells MDA-MB-231 were taken and divided into normal saline （NS） group, low-dose fritinib （LD） group, medium-dose fritinib （MD） group and high-dose fritinib （HD） group. NS group was added with 100 μmol/L normal saline. LD group, MD group and HD group were added with 25, 50 and 100 μmol/L fritinib, respectively. Cell proliferation was detected by MTT assay, cell apoptosis was detected by flow cytometry, the ability of cells to form mimicry vessels was observed by three-dimensional cell culture, and the related indexes of angiogenesis and IRE1-ASK1-JNK pathway were detected by Western blotting. Twenty triple-negative breast cancer rat models were divided into control group and experimental group by random number table method, with 10 rats in each group. The control group was given normal saline gavage and the experimental group was given 100 μmol/L fritinib gavage. The tumor growth of rats in the two groups was observed and recorded. Results The 48 h cell proliferation rates of NS group, LD group, MD group and HD group were （85.44±5.58）%, （73.24±4.95）%, （61.53±4.07）% and （50.23±2.97）%, respectively （F=4.01, P=0.002）. Compared with the NS group, the cell proliferation rate in LD, MD and HD groups was significantly decreased in a dose-dependent manner （all P<0.05）. The apoptosis rates of NS group, LD group, MD group and HD group were （3.41±0.39）%, （18.75±1.94）%, （24.97±2.58）% and （38.62±3.27）%, respectively （F=18.99, P<0.001）. Compared with the NS group, the apoptosis rate of LD, MD and HD groups was significantly increased in a dose-dependent manner （all P<0.05）. The number of mimicry vessels in NS group, LD group, MD group and HD group was 19.58±2.11, 15.67±2.02, 11.57±1.73 and 5.20±1.23, respectively （F=3.28, P=0.008）. Compared with the NS group, the number of mimicry vessels in LD group, MD group and HD group was significantly reduced. The results were dose-dependent （all P<0.05）. vascular endothelial growth factor （VEGF） protein expression in NS group, LD group, MD group and HD group was 2.36±0.21, 1.79±0.17, 1.48±0.14 and 0.94±0.10, respectively （F=5.17, P<0.001）. The expression of IRE1 protein was 1.18±0.12, 1.67±0.18, 2.03±0.24 and 2.39±0.28, respectively （F=5.55, P<0.001）. The expression of ASK1 protein was 1.09±0.11, 1.46±0.13, 1.81±0.18, 2.33±0.21 （F=5.32, P<0.001）, respectively. JNK protein expression was 1.01±0.09, 1.48±0.14, 1.86±0.21 and 2.28±0.24, respectively （F=6.92, P<0.001）. Compared with the NS group, VEGF protein expression in LD, MD and HD groups was significantly decreased, and the expressions of IRE1, ASK1 and JNK were significantly increased in a dose-dependent manner （all P<0.05）. Compared with the control group, the tumor weight and volume of the experimental group were significantly decreased [（0.55±0.10）g vs. （1.37±0.15）g, t=14.38, P<0.001； （77.39±3.21）mm³ vs. （118.26±5.34）mm³, t=20.74, P<0.001], tumor inhibition rate was significantly increased [（71.23±3.85）% vs. （32.56±3.08）%, t=24.80, P<0.001]. Conclusion Fritinib has an inhibitory effect on the activity of triple negative breast cancer cells, which can significantly reduce their angiogenesis and inhibit tumor growth. Moreover, it is related to the activation of IRE1-ASK1-JNK pathway.

Key words: Triple negative breast neoplasms, Fritinib, Angiogenesis, Tumor growth, IRE1-ASK1-JNK path