인체위암세포주 (AGC)의 증식에 미치는 lovastatin의 억제효과 (The effect of Lovastatin on the Human Gastric Carcinoma Cells)

서지정보

· 발행기관 : 고신대학교(의대) 고신대학교 의과대학 학술지
· 수록지 정보 : 고신대학교 의과대학 학술지 / 17권 / 1호 / 8 ~ 17페이지
· 저자명 : 김지연, 김성훈, 서수홍, 최병주, 김현영, 노치환, 김동완, 김기환, 박무인, 구자영

초록

Background : At the first step of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) catalyzes the formation of mevalonate, which is the precusor of isoprenoid moieties that are incorporated into or linked to several molecules for cell growth and replication, which include Ras, Rho, G proteins and nuclear laminin B. Lovastatin (mevinolin), as an inhibitor of HMG-CoA reductase, blocks mevalonate synthesis, by which also prevents the isoprenylation of several proteins such as Ras, display antitumor effect in experimental models. In the present study the isoprenylation of several proteins such as Ras, display antitumor effect in experimental models. In the present study the effects of lovastatin on the growth of human gastric carcinoma cell line, AGS cells were examined and the effects of 5-fluorouracil (5-FU) were also stuided. Cell cycle analysis was done to examine the mechanisms for the inhibitory effects of lovastatin.
Methods : The growth of ACS cells were examined by counting cell number on one and three days treatment with 0.2 umol/L, 0.4 umol/L, 0.8 umol/L, 1.6 umol/L, 3.2 umol/L lovastatin, and 0.1 ug/ml, 0.3 ug/ml 5-FU, after plating AGS cells into 35n㎡ plastic dishes at a density of 10*10^4 cells/dish. The reversibility of the effects of lovastatin was examined on one day to seven days treatment with 0.8 umol/L lovastatin after seeding 10*10^4 cells/dish. To examine the mechanisms for the inhibitory effects of lovastatin, cell cycle analysis was done on the cells after four days treatment with 0.8 umol/L lovastatin.
Results : Lovastatin significantly inhibited the growth of AGS cells in a dose-dependent fashion (p<0.05). Forty-eight percent inhibiton of growth was found at an lovastatin concentration of 0.8 umol/L and ninety-three percent inhibition of growth was found at an lovastatin concentration of 3.2 umol/L after 4 days treatment. The inhibitory effect of media change after 24 hours treatment of lovastatin was note different from that of control group, which was not treated by lovastatin. Lovastatin combined with 5-FU significantly inhibited the growth of AGS cells in a dose-dependent fashion compraed to lovastatin or 5-FU alone (p<0.05), which suggested additive effect of the two drugs. After four days treatment with 0.8 umol/L lovastatin, the fraction of cells in G0-G1 phase, S phase and G2-M phase was 51.5%, 31.5%, 17.0% respectively in the control group, and 50.6%, 32.6%, 16.7% in the lovastatin group (0.8 umol/L), showing no significant differences between the two.
Conclusions : Lovastatin significantly inhibited the growth of AGS cells in a dose-dependent fashion. The inhibitory effect for lovastatin on the growth of AGS cells was reversible since the growth of AGS cells after removal of lovastatin by a media change after 24-48 hours treatment of lovastatin was note different from that of control group which was note treated by lovastatin. The reversibility of growth inhibition suggests that lovastatin is not a non-specific cytotoxin for AGS cells. This is the first report that lovastatin may be very useful for the treatment of gastric carcinoma, especially in conjunction with 5-FU, because the concentrations (0.2-3.2 umol/L) used in our study were within the ranges of steady-state concentrations (0.15-0.3 umol/L) attainable in human serum by chronic administration of maximum recommended dose (80 mg/day) of lovastatin and additive effect of lovastatin and 5-FU. More studies by animal experiments and clinical trials are needed to establish lovastatin as an anticancer drug for human gastric carcinoma.

영어초록

Background : At the first step of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) catalyzes the formation of mevalonate, which is the precusor of isoprenoid moieties that are incorporated into or linked to several molecules for cell growth and replication, which include Ras, Rho, G proteins and nuclear laminin B. Lovastatin (mevinolin), as an inhibitor of HMG-CoA reductase, blocks mevalonate synthesis, by which also prevents the isoprenylation of several proteins such as Ras, display antitumor effect in experimental models. In the present study the isoprenylation of several proteins such as Ras, display antitumor effect in experimental models. In the present study the effects of lovastatin on the growth of human gastric carcinoma cell line, AGS cells were examined and the effects of 5-fluorouracil (5-FU) were also stuided. Cell cycle analysis was done to examine the mechanisms for the inhibitory effects of lovastatin.
Methods : The growth of ACS cells were examined by counting cell number on one and three days treatment with 0.2 umol/L, 0.4 umol/L, 0.8 umol/L, 1.6 umol/L, 3.2 umol/L lovastatin, and 0.1 ug/ml, 0.3 ug/ml 5-FU, after plating AGS cells into 35n㎡ plastic dishes at a density of 10*10^4 cells/dish. The reversibility of the effects of lovastatin was examined on one day to seven days treatment with 0.8 umol/L lovastatin after seeding 10*10^4 cells/dish. To examine the mechanisms for the inhibitory effects of lovastatin, cell cycle analysis was done on the cells after four days treatment with 0.8 umol/L lovastatin.
Results : Lovastatin significantly inhibited the growth of AGS cells in a dose-dependent fashion (p<0.05). Forty-eight percent inhibiton of growth was found at an lovastatin concentration of 0.8 umol/L and ninety-three percent inhibition of growth was found at an lovastatin concentration of 3.2 umol/L after 4 days treatment. The inhibitory effect of media change after 24 hours treatment of lovastatin was note different from that of control group, which was not treated by lovastatin. Lovastatin combined with 5-FU significantly inhibited the growth of AGS cells in a dose-dependent fashion compraed to lovastatin or 5-FU alone (p<0.05), which suggested additive effect of the two drugs. After four days treatment with 0.8 umol/L lovastatin, the fraction of cells in G0-G1 phase, S phase and G2-M phase was 51.5%, 31.5%, 17.0% respectively in the control group, and 50.6%, 32.6%, 16.7% in the lovastatin group (0.8 umol/L), showing no significant differences between the two.
Conclusions : Lovastatin significantly inhibited the growth of AGS cells in a dose-dependent fashion. The inhibitory effect for lovastatin on the growth of AGS cells was reversible since the growth of AGS cells after removal of lovastatin by a media change after 24-48 hours treatment of lovastatin was note different from that of control group which was note treated by lovastatin. The reversibility of growth inhibition suggests that lovastatin is not a non-specific cytotoxin for AGS cells. This is the first report that lovastatin may be very useful for the treatment of gastric carcinoma, especially in conjunction with 5-FU, because the concentrations (0.2-3.2 umol/L) used in our study were within the ranges of steady-state concentrations (0.15-0.3 umol/L) attainable in human serum by chronic administration of maximum recommended dose (80 mg/day) of lovastatin and additive effect of lovastatin and 5-FU. More studies by animal experiments and clinical trials are needed to establish lovastatin as an anticancer drug for human gastric carcinoma.

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