Dilazep, a nucleoside transporter inhibitor, modulates cell cycle progression and DNA synthesis in rat mesangial cells in vitro

Abstract

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.

Effects of the Anti-Platelet Aggregation Drug Dilazep on Cognitive Function in Dahl Salt-Sensitive Rats.

“…In this context, we demonstrated that dilazep treatment indeed attenuated glomerular sclerosis, suggesting that the vascular protection was observed throughout the systemic circulation. In addition, it has been well documented that dilazep, a nucleoside transporter inhibitor, behaves as an anti-platelet aggregatory drug and an oxygen-radical scavenger, and prevents the appearance of neurological symptoms and brain damage induced by ischemia and reperfusion (5)(6)(7)(8)(9)(10)(11). Unfortunately, we were unable to provide evidence that the scavenging effects of dilazep participated in the preservation of cognition.…”

“…In addition, this drug uniquely behaves in vitro as an oxygen-radical scavenger (7). Such multifactorial actions are believed to attenuate mesangial cell proliferation or glomerular injury in immunoglobulin A (IgA) nephropathy (8)(9)(10). More interestingly, dilazep is reported to prevent the appearance of neurological symptoms and brain damage induced by ischemia following carotid artery occlusion and reperfusion, probably through suppression of lipid peroxidation (11).…”

A Metal-containing Nucleoside That Possesses Both Therapeutic and Diagnostic Activity against Cancer

“…In addition, inhibiting nucleoside transporter activity does not typically block cell cycle progression at G 2 /M. For example, Sakumura et al (36) showed that dilazep, an adenosine uptake inhibitor, blocks cells at both G 1 and S phase. Thus, the unique effects of Ir(III)-PPY nucleoside on cell cycle progression prompted us to further investigate its activity against KB3-1 cells synchronized at G 1 by treatment with L-mimosine (37).…”