CDK1 hyperphosphorylation maintenance drives the time-course of G2-M cell cycle arrest after short treatment with NAMI-A in Kb cells.

Abstract

We investigated the molecular events of the ruthenium complex NAMI-A (0.1 mM for 1 h) on cell cycle G2-M arrest in KB carcinoma cells. Flow cytometry analysis showed a progressive accumulation of cells in S phase at 16 h, and in G2-M phase at 20 h after the end of treatment. NAMI-A pre-mitotic stop to cell proliferation was due to the maintenance of the phosphorylated, inactive, form of Cdk1, caused by the activation of the ATM/ATR checkpoint, as confirmed by the up-regulation and phosphorylation of Chk1. All these events are related to intracellular ruthenium accumulation, as confirmed by the lack of similar effects in cell lines unable to take the ruthenium compound up. Considering the dependence of NAMI-A cell cycle arrest on the dose and on the length of cell challenge, and considering the prolonged NAMI-A t1/2 in vivo in the lungs, we proved an even greater perturbation of the cell cycle regulating pathways in lung metastases of NAMI-A treated mice. The ex-vivo data confirm the interaction of the ruthenium compound NAMI-A with the ATM/ATR pathway, leading to the modulation of cell cycle regulating proteins, that can break the metastases cell cycle progression off.

• Authors: Alberta Bergamo, Riccarda Delfino, Claudia Casarsa, Gianni Sava
• Journal: Anti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 12 Issue 8 Pg. 949-58 (Oct 01 2012) ISSN: 1875-5992 [Electronic] Netherlands
• PMID: 22263785 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Organometallic Compounds
• Ruthenium Compounds
• imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III)
• CDC2 Protein Kinase
• Dimethyl Sulfoxide

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• CDC2 Protein Kinase (antagonists & inhibitors, metabolism)
• Cell Cycle (drug effects)
• Cell Division (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dimethyl Sulfoxide (analogs & derivatives, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• G2 Phase (drug effects)
• HeLa Cells
• Humans
• Organometallic Compounds (chemistry, pharmacology)
• Phosphorylation (drug effects)
• Ruthenium Compounds
• Structure-Activity Relationship
• Time Factors