Dilazep, a nucleoside transporter inhibitor, modulates cell cycle progression and DNA synthesis in rat mesangial cells in vitro.
The direct effects of the nucleoside transporter inhibitor dilazep on the cell cycle of mesangial cells have not before been investigated. The purpose of this study was to elucidate whether dilazep can inhibit the proliferation of mesangial cells and how it interferes with the cell cycle of these cells. DNA histograms were used and BrdUrd uptake rate was measured by flow cytometry. There was no significant difference in the cell numbers among the untreated group and the 10(-5) M, 10(-6) M or 10(-7) M dilazep-treated groups at 24 h of incubation. However, at 48 and 72 h, the cell numbers in the dilazep-treated groups were significantly lower compared with that of the untreated group (P < 0.005). The DNA histograms of cultured rat mesangial cells at 12, 24, and 48 h of incubation with 10(-5) M dilazep showed that the ratio of the S phase population in the dilazep-treated group decreased by 2.2% at 12 h, by 9.6% at 24 h, and by 18.9% at 48 h compared with the untreated group. The ratio of the G0/G1 phase population in the dilazep-treated group significantly increased: 6.8% at 12h (P < 0.05), 13.9% at 24 h (P < 0.001), and 76.5% at 48 h (P < 0.001) compared with the untreated group. A flow cytometric measurement of bivariate DNA/BrdUrd distribution demonstrated that the DNA synthesis rate in the S phase decreased after 6 h (P < 0.005) and 12 h (P < 0.05) of incubation compared with the untreated group. These results suggest that dilazep inhibits the proliferation of cultured rat mesangial cells by suppressing the G1/S transition by prolonging G2/M and through decreasing the DNA synthesis rate.
Sakumura
T
T
The Second Department of Internal Medicine, Yamaguchi University School of Medicine, Ube, Japan.
Fujii
Z
Z
Umemoto
S
S
Murakami
T
T
Kawata
Y
Y
Fujii
K
K
Minami
M
M
Sasaki
K
K
Matsuzaki
M
M
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis*; D004109:Dilazep / Q000494:pharmacology*; D005434:Flow Cytometry; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D033703:Nucleoside Transport Proteins; D009705:Nucleosides / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016196:S Phase / Q000187:drug effects
D002352:Carrier Proteins; D008565:Membrane Proteins; D033703:Nucleoside Transport Proteins; D009705:Nucleosides; D004247:DNA; D004109:Dilazep; D001973:Bromodeoxyuridine