Effects of simvastatin on the proliferation, invasion and radiosensitivity in Lewis lung cancer cell line

Abstract

Objective: To investigate the effects of simvastatin on proliferation, invasion and radiosensitivity of mouse Lewis lung cancer cell line in vitro. Methods: The inhibitory effects of simvastatin on proliferation of Lewis lung cancer cells were detected by MTT assay. Matrigel invasion and migration assay was used to determine the invasion and motility ability of the Lewis cells. P38 activity was measured by p38 activity detection kit, and the expressions of p-p38, MKP-1, RhoA and MMP-2 were analyzed by Western blot. Lung cancer xenograft model was established in C57BL/6 mice. The mice were randomly divided into control group, simvastatin group, radiotherapy alone group and combined treatment group. The mice were killed 27 days after inoculation. The tumor mass, volume and lung metastatic nodules in the mice were compared. Results: The cell proliferation rates of 0 μmol/L, 10 μmol/L, 20 μmol/L and 30 μmol/L simvastatin groups were 100%, (87.0±9.0)%, (76.5±8.1)% and (67.0±7.3)%, respectively (P<0.05). Invasive cell numbers of the above groups were 298±30, 251±26, 207±20 and 132±19 per field, respectively (P<0.05). The intracellular p38 activities were 100%, (83.1±8.8)%, (70.2±8.2)% and (59.0±6.4)%, respectively. The relative expressions of p-p38 were 100%, (76.2±6.7)%, (56.4±5.4)% and (36.5±3.2)%, respectively. The expressions of RhoA were 100%, (80.1±5.3)%, (55.3±6.2)% and (38.6±4.8)%, respectively. The expressions of MMP-2 were 100%, (89.6±8.6)%, (51.9±4.7)% and (42.7±3.1)%, respectively, while the expressions of MKP-1 were 100%, (136.5±12.2)%, (168.8±15.3)% and (187.7±13.4)%, respectively (all P<0.05). Lung metastatic nodules and mass in the control, simvastatin, radiotherapy group and combined treatment groups were 6.24±1.09, 3.07±0.71 g, 5.09±1.16, 2.43±0.53 g, 3.12±0.68, 1.96±0.62 g and 2.65±0.38, 1.12±0.43 g, respectively (all P<0.05). The tumor inhibition rates were 39.0%, 48.1% and 26.5%, respectively, in the radiotherapy alone, combined treatment and simvastatin groups (all P<0.05). Conclusions: Simvastatin inhibits the proliferation of Lewis cell line by inhibiting the activity of p38 and expression of p-p38. Meanwhile, simvastatin reduces the invasion and motility of Lewis cell line through down-regulating the expression of RhoA and MMP-2. When combined with radiotherapy, simvastatin can inhibit tumor growth and metastasis, and improve the treatment efficacy of radiotherapy synergistically.