Inhibitory effect of NVP-BEZ235 on gastric cancer in nude mice

Abstract

Objective To investigate the effect of NVP-BEZ235 alone and combined with 5-fluorouracil (5-Fu) on NCI-N87 gastric cancer in nude mice. Methods human gastric cancer cell line NCI-N87 was used to prepare tumor bearing mice. Divided into control group (normal saline every 3 days 0.02 ml/g, every 3 days by intraperitoneal injection of saline 0.02 ml/g), group 5-Fu (normal saline every 3 days every 3 days by intraperitoneal injection of 0.02 ml/g, 5-Fu 0.025 mg/g), group NVP-BEZ235 (every 3 days by gavage once every 3 days NVP-BEZ235 0.04 mg/g, intraperitoneal injection of saline.0.02 ml/g), combination group (gavage once every 3 days NVP-BEZ235 0.04 mg/g, every 3 days by intraperitoneal injection of 5-Fu 0.025 mg/g). Recorded the volume and weight of tumor. Detection of apoptosis related proteins, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway related proteins and invasion related proteins by Western blotting. Results Compared with 5-Fu group (6.84±0.98), the relative volume of tumor in nude mice with NCI-N87 gastric cancer xenograft model was (8.47±1.44), and the difference was statistically significant (t=2.303, P=0.044)). Tumor weight (g): the combination group (0.83±0.16) was less than the 5-Fu group (1.20±0.32), the difference was statistically significant (t=2.524, P=0.038). Akt, p-Akt, the relative expression of mTOR in group NVP-BEZ235 (0.56±0.05, 0.23±0.04, 0.50±0.03) was significantly lower than the control group (0.96±0.11, 0.68±0.03, 0.64±0.12; t=9.739, 21.823, 3.366, P=0.000, 0.000, 0.006)), combination group (0.53±0.06, 0.20±0.03, 0.51±0.07) was significantly lower than that of group 5-Fu (0.93±0.10, 0.51±0.05, 0.67±0.04; t=8.234, 12.489, 4.628, P=0.000, 0.000, 0.002), there was significant difference between the four groups (F=46.457, 263.318, 6.678, P=0.000, 0.000, 0.002). The activation of apoptosis related protein cysteinyl aspartate-specific protease (Caspase)-3, B cell lymphoma/leukemia-2 associated X protein (bax) and B cell lymphoma/leukemia-2 (bcl-2), NVP-BEZ235 (1.28±0.06, 1.39±0.08, 0.59±0.04) was significantly higher than the control group (0.94±0.10, 0.99±0.11, 1.07±0.07; t=8.660, 8.077, 17.456, P=0.000, 0.000, 0.000) combined. The medicine group (1.57±0.09, 1.70±0.10, 0.37±0.07) was significantly higher than that of group 5-Fu (1.42±0.09, 1.50±0.05, 0.48±0.07; t=2.737, 4.472, 2.861, P=0.021, 0.003, 0.017), compared with a significant difference between the four groups (F=71.181, 81.393, 199.848, P=0.000, 0.000, 0.000). The relative expression of matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF), NVP-BEZ235 (0.44±0.04, 0.30±0.05) was significantly lower than the control group (0.59±0.06, 0.41±0.03; t=5.335, 5.550, P=0.000, 0.001), combination group (0.37±0.04, 0.24±0.07) was significantly lower than that of 5-Fu group (0.58±0.12, 0.36±0.04; t=4.144, 3.691, P=0.006, 0.005), compared with a significant difference between the four groups (F=15.164, 20.205, P=0.000, 0.000). Conclusion NVP-BEZ235 can down regulate the activation level of PI3K/Akt/mTOR pathway, promote apoptosis, inhibit tumor invasion and metastasis, and play a synergistic role with 5-Fu. Key words: Gastric cancer; NVP-BEZ235; Phosphatidylinositol 3 kinase/protein kinase B/mammalian target of rapamycin signaling pathway; Apoptosis; Invasion