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Study on the Inhibitory Effects and Mechanism of New Small Molecular Kinase Inhibitors Ibr- 7 on Human Pancreatic Cancer Capan-2 Cells / 中国药房
China Pharmacy ; (12): 499-506, 2019.
Article in Chinese | WPRIM | ID: wpr-817095
ABSTRACT
OBJECTIVE: To observe the inhibitory effects and possible mechanism of new small molecular kinase inhibitors Ibr-7 [Irutinil(Ibr) derivatives] on human pancreatic cancer Capan-2 cells. METHODS: Taking Capan-2 cells as objects, CCK-8 method was used to determine the proliferation of cells after treated with 1, 2, 4, 8 μmol/L Ibr/Ibr-7 for 48 h. The survival rates of cells were calculated. Sensitization effects of 1 μmol/L Ibr/Ibr-7 on different doses of gemcitabine/paclitaxel (0.062 5, 0.125, 0.25, 0.5, 1 μmol/L) were detected. Clone formation test was used to detect the situation of cell clone formation after treated with 1, 2, 4 μmol/L Ibr/Ibr-7 for 48 h. The number of cell colony formation was recorded. Flow cytometry or JC-1 method was used to detect the apoptosis of cells after treated with 2, 4, 8 μmol/L Ibr-7 for 24 or 16 h and the changes of mitochondrial transmembrane potential; total apoptotic rate and the percentage of mitochondrial membrane potential decrease were calculated. Western blotting was used to detect the expression of related apoptotic protein (PARP, Noxa, Bcl-2, Bax, Mcl-1, Bcl-xL). RESULTS: After treated with 1, 2, 4, 8 μmol/L Ibr/Ibr-7 for 48 h, the survival rates of cells were decreased significantly; those of Ibr-7 groups were significantly lower than those of same-dose Ibr groups; IC50 of Ibr-7 was significantly lower than that of Ibr (P<0.05 or P<0.01). After combined with Ibr/Ibr-7, the survival rate of cells was significantly lower than that of same-dose gemcitabine/paclitaxel alone group, and the Ibr-7 combination group was significantly lower than same-dose Ibr combination group (P<0.05 or P<0.01). After treated with 2, 4 μmol/L Ibr and 1, 2, 4 μmol/L Ibr-7 for 48 h, the number of cell clone formation was decreased significantly, while Ibr-7 groups were significantly lower than same-dose Ibr groups (P<0.01). After treated with different doses of Ibr-7 for 24 or 16 h, total apoptosis rate of cells (2, 4, 8 μmol/L), the proportion of cell mitochondrial membrane potential decrease (8 μmol/L), the relative protein expression of Noxa (2, 4, 8 μmol/L) and Bax (8 μmol/L) were increased significantly, while the protein expression of PARP (8 μmol/L), Bcl-2 (4 μmol/L), Mcl-1 (2, 4, 8 μmol/L) were decreased significantly; above indexes (except for relative expression of PARP and Bcl-2) of 8 μmol/L Ibr-7 group were significantly better than same-dose Ibr group (P<0.05 or P<0.01). There was no statistical significance in protein expression of Bcl-xL among those groups (P>0.05). CONCLUSIONS: Compared with Ibr, Ibr-7 has better inhibitory and apoptotic effects on human pancreatic cancer Capan-2 cells in vitro, and has stronger chemotherapeutic drug sensitization activity, the mechanism of which may be associated with reducing mitochondrial transmembrane potential, down-regulating the protein expression of PARP, Bcl-2 and Mcl-1 and up-regulating the protein expression of Noxa and Bax.

Full text: Available Index: WPRIM (Western Pacific) Language: Chinese Journal: China Pharmacy Year: 2019 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Language: Chinese Journal: China Pharmacy Year: 2019 Type: Article