Objective       To investigate the effects of a proteasome inhibitor bortezomib on the proliferation

cell cycle and tumor formation of human lung adenocarcinoma A549 cells

and to explore the possible mechanisms involved.       Methods       Human lung adenocarcinoma A549 cells were cultured and treated with different concentrations of bortezomib (0

100 and 200 nmol/L) for 4 h

and the

proteasome activity were measured to confirm its inhibitory effects. The A549 cells were further treated with different concentrations of bortezomib (0

100 and 200 nmol/L) for 24-48 h. Cell proliferation was determined by MTT assay and

3

H-TdR absorption

respectively. Cell cycle was detected by flow cytometry

and the protein levels of p21 and p27 were determined by Western blotting. A549 cells were implanted subcutaneously into nude mice to establish the xenograft tumor models

and the xenograft tumor bearing mice were subjected to bortezomib. The tumor volume and weight in all groups were measured

and the tumor inhibitory rate was calculated.       Results       Bortezomib significantly inhibited the proteasome activity in A549 cells. The MTT and

3

H-TdR results showed that cell proliferation decreased by 24.5% and 29.5% in the 100 nmol/L bortezomib group

respectively

and a more significant decease was observed in the 200 nmol/L bortezomib group compared with the control group (P0.05). Cell cycle analysis showed that the number of cells at G

0

/G

1

phase was significantly increased in the 100 nmol/L and 200 nmol/L bortezomib groups compared with the control group (P0.05). Western blot results showed that p21 and p27 significantly increased in a dose-dependent manner in the 100 nmol/L and 200 nmol/L bortezomib groups compared with the control group (P0.05). In addition

the levels of p21 and p27 in the bortezomib group were significantly higher at 48 h than those at 24 h. After continuous injection

the weight of the xenograft tumors was reduced by (36.0±12.4)% in the bortezomib group compared with the control group.       Conclusion       Bortezomib can inhibit A549 cell proliferation and induce cell cycle arresting at G

0

/G

1

phase

probably by inhibiting the degradation of p21 and p27 proteins in A549 cells.