关键词: 索拉菲尼, 吡咯烷二硫代氨基甲酸盐, 细胞增殖, 细胞周期, 核转录因子-&kappa, B

Abstract:

Background and purpose: Sorafenib, a multiple targeted agent, can inhibit proliferation and induce apoptosis of diverse tumor cell in vitro. It has extensive biological activities, but the pancreatic cancer effect of monotherapy is poor. This may be related to nuclear factor-kappa B (NF-κB) pathway activation in cancer. Therefore, it is necessary to combine with Pyrrolidinedithiocarbamate (PDTC, a NF-κB activation inhibitor) to enhance curative effect. To investigate the influences of cell proliferation, cell cycle and expression of NF-κB via their acting on human pancreatic cancer PANC-1, and explore their possible mechanism. Methods: The experiment groups were divided into sorafenib group with different concentrations (1.5, 3.0, 6.0, 12.0 μmol/L), PDTC group with different concentrations (10.0, 25.0, 50.0, 100.0 μmol/L) and combination group with low concentration (3.0 μmol/L sorafenib +25.0 μmol/L PDTC). The proliferative activity of PANC-1 of each group was measured by MTT assay at different time points of 24, 36, 48 and 72 h, and the half inhibitory concentration (IC₅₀) was calculated, respectively. Cell cycle in each group was detected by flow cytometry instrument after 48 h. The changes of NF-κB expression level in each group were observed by immunocytochemistry after 24 h. Results: Sorafenib and PDTC can significantly inhibit the proliferation of PANC-1, but IC₅₀ value of the single medicine was higher, combination group with low concentration can significantly increase the cell growth inhibition rate (P<0.05). Three groups can induce the cell stagnation at G₀/G₁ phase (P<0.05) and cells at S phase were decreased. The effect of combination group with low concentration was better than the single drug group (P<0.05). The NF-κB expression level in sorafenib group was significantly enhanced, while the level in combination group was significantly decreased (P<0.05). Conclusion: Sorafenib and PDTC can significantly inhibit the growth of human pancreatic cancer PANC-1 cells in vitro, but the effect of one drug is unsatisfactory. PDTC combined with sorafenib significantly improve the inhibition rate of the proliferation of human pancreatic cancer PANC-1, and induce the cell stagnation at G₀/G₁ phase. This may relate to inhibit the activation of NF-κB by PDTC and enhance the sensitivity of PANC-1 cells to sorafenib.

Key words: Sorafenib, Pyrrolidinedithiocarbamate, Cell proliferation, Cell cycle, NF-κB