Cyclin-dependent kinase inhibitors block proliferation of human gastric cancer cells

Iseki, Hideaki; Ko, Tien C.; Xue, Xiang; Seapan, Annie; Hellmich, Mark R.; Townsend, Courtney M.

doi:10.1016/s0039-6060(97)90008-8

Cited by 44 publications

(34 citation statements)

References 18 publications

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“…It should be emphasized, however, that cdk inhibitors block multiple cellular activities, such as cell division (38,56), which are essential in healthy animals or humans. Thus, viral diseases that may be treated with these drugs must be identified with great care.…”

Section: Discussionmentioning

confidence: 99%

“…Rosco and Olo specifically inhibit a subset of cdks which includes cdk-1, cdk-2, and cdk-5 but not cdk-4 or cdk-6. In vivo, Rosco inhibits cell cycle progression at concentrations between 10 and 100 M, depending on the cell line used (2,38,56). This inhibition of cell cycle progression has been determined to be mediated by inhibition of cdk-1 and cdk-2 activities (2,56).…”

mentioning

confidence: 99%

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Roscovitine, a Specific Inhibitor of Cellular Cyclin-Dependent Kinases, Inhibits Herpes Simplex Virus DNA Synthesis in the Presence of Viral Early Proteins

Schang

Rosenberg

Schaffer

2000

J Virol

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We have previously shown that two inhibitors specific for cellular cyclin-dependent kinases (cdks), Roscovitine (Rosco) and Olomoucine (Olo), block the replication of herpes simplex virus (HSV). Based on these results, we demonstrated that HSV replication requires cellular cdks that are sensitive to these drugs (L. M. Schang, J. Phillips, and P. A. Schaffer. J. Virol. 72:5626-5637, 1998). We further established that at least two distinct steps in the viral replication cycle require cdks: transcription of immediate-early (IE) genes and transcription of early (E) genes (L. M. Schang, A. Rosenberg, and P. A. Schaffer, J. Virol. 73:2161-2172, 1999). Since Rosco inhibits HSV replication efficiently even when added to infected cells at 6 h postinfection, we postulated that cdks may also be required for viral functions that occur after E gene expression. In the study presented herein, we tested this hypothesis directly by measuring the efficiency of viral replication, viral DNA synthesis, and expression of several viral genes during infections in which Rosco was added after E proteins had already been synthesized. Rosco inhibited HSV replication, and specifically viral DNA synthesis, when the drug was added at the time of release from a 12-h phosphonoacetic acid (PAA)-induced block in viral DNA synthesis. Inhibition of DNA synthesis was not a consequence of inhibition of expression of IE or E genes in that Rosco had no effect on steady-state levels of two E transcripts under the same conditions in which it inhibited viral DNA synthesis. Moreover, viral DNA synthesis was inhibited by Rosco even in the absence of protein synthesis. In a second series of experiments, the replication of four HSV mutants harboring temperature-sensitive mutations in genes essential for viral DNA replication was inhibited when Rosco was added at the time of shift-down from the nonpermissive to the permissive temperature. Viral DNA synthesis was inhibited by Rosco under these conditions, whereas expression of viral E genes was not affected. We conclude that cellular Rosco-sensitive cdks are required for replication of viral DNA in the presence of viral E proteins. This requirement may indicate that HSV DNA synthesis is functionally linked to transcription, which requires cdks, or that both viral transcription and DNA replication, independently, require viral or cellular factors activated by Rosco-sensitive cdks.Herpes simplex virus (HSV) replicates in both cycling and noncycling cells, including terminally differentiated neurons. HSV replication, however, requires cellular functions associated with cell cycle progression. Thus, HSV replicates more efficiently in actively dividing than growth-arrested cells. This difference in replication efficiency is especially prominent among viral mutants which lack specific viral functions such as those provided by the regulatory proteins ICP0 and VP16 or by enzymes involved in nucleotide metabolism, such as thymidine kinase (TK) or ribonucleotide reductase (9, 16, 25). The dependence on cell cycle-activat...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Roscovitine, a Specific Inhibitor of Cellular Cyclin-Dependent Kinases, Inhibits Herpes Simplex Virus DNA Synthesis in the Presence of Viral Early Proteins

Schang

Rosenberg

Schaffer

2000

J Virol

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“…Roscovitine, an inhibitor of CDKs, has been used for control of the cell cycle [51][52][53]. Previous studies indicate that ROS arrests normal somatic cells in the G0/G1 stage [29,52,54], but it arrests tumor cells in the G2/M phase [55][56][57]. Our results showed that ROS arrested MFFCs in the G0/G1 phase in a concentration-and durationdependent manner.…”

Section: Discussionmentioning

confidence: 53%

Effects of Cell Cycle Status on the Efficiency of Liposome-mediated Gene Transfection in Mouse Fetal Fibroblasts

Miao

et al. 2006

Journal of Reproduction and Development

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Abstract. Methods for cell cycle synchronization of mouse fetal fibroblast cells (MFFCs) were first selected and optimized. When MFFCs were cooled at 5 C for different periods of time, the highest percentage of cells at the G0/G1 phase (75.4 ± 2.9%), with 3.5 ± 0.3% of apoptotic cells, was achieved after 5 h of treatment. Extended cooling increased the number of apoptotic cells significantly. When MFFCs were treated with different concentrations of roscovitine (ROS) for different periods of time, the highest percentage of G0/G1 cells (83.5 ± 1.8%), with 9.2 ± 0.6% apoptotic cells, was obtained after exposure to 10 µM ROS for 24 h. When the cells were cooled at 5 C for 5 h followed by incubation in 10 µM ROS for 12 h, 83.6 ± 1.9% were synchronized at the G0/G1 stage, with 3.6% undergoing apoptosis. Cell cycle progression was then observed after release of the MFFCs from different synchronization blocks. The highest percentages of S and G2/M cells (81% and 75%) were achieved at 12 and 20 h, respectively, after release of the MFFCs from the cooling plus ROS treatment, and these percentages were significantly higher than those obtained after release from the cooling or ROS alone blocks. Finally, MFFCs were transfected with pEGFP-N1 plasmid at the peak of the G0/G1, S, and G2/M phases, respectively, after release from the different blocks and both the transient and stable transfection efficiencies were determined. The GFP gene expression was greatly enhanced when transfection was performed at the time when most cells were at the G2/M stage after release from cooling, ROS alone, and cooling plus ROS treatments. Statistical analysis revealed a close correlation between the rate of G2/M cells and the transient and stable GFP gene expression efficiencies. Together, the results indicated that (a) the best protocol for cell cycle synchronization of MFFCs was a 5-h cooling at 5 C followed by incubation in 10 µM ROS for 12 h which produced both a high rate of synchronization in the G0/G1 phase with acceptable apoptosis and a high rate of G2/M cells after release; and (b) that the cell cycle status had marked effects on the efficiency of liposome-mediated transfection in MFFCs, with the highest transfection efficiency obtained in cells at the G2/M stage.

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“…This is known to occur through mutation in genes that produce regulatory proteins which modulate cell cycle, such as the Cyclin Dependent Kinases (Cdks) [14][15][16]. Cdks are highly conserved serine/threonine kinases whose activation depends on formation of a heterodimeric complex with cyclins [17][18][19]. Thus, Cdks are a promising therapeutic target for cancer treatment [20].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling of Anti-Neoplastic Agents

Lexcen¹,

Salem²,

Elkhatib³

et al. 2012

Readings in Advanced Pharmacokinetics - Theory, Methods and Applications

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Cyclin-dependent kinase inhibitors block proliferation of human gastric cancer cells

Cited by 44 publications

References 18 publications

Roscovitine, a Specific Inhibitor of Cellular Cyclin-Dependent Kinases, Inhibits Herpes Simplex Virus DNA Synthesis in the Presence of Viral Early Proteins

Roscovitine, a Specific Inhibitor of Cellular Cyclin-Dependent Kinases, Inhibits Herpes Simplex Virus DNA Synthesis in the Presence of Viral Early Proteins

Effects of Cell Cycle Status on the Efficiency of Liposome-mediated Gene Transfection in Mouse Fetal Fibroblasts

Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling of Anti-Neoplastic Agents

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