CDK1 Hyperphosphorylation Maintenance Drives the Time-course of G2-M Cell Cycle Arrest after Short Treatment with NAMI-A in Kb Cells

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)


Volume 16, 12 Issues, 2016


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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex
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CDK1 Hyperphosphorylation Maintenance Drives the Time-course of G2-M Cell Cycle Arrest after Short Treatment with NAMI-A in Kb Cells



Anti-Cancer Agents in Medicinal Chemistry, 12(8): 949-958.

Author(s): Alberta Bergamo, Riccarda Delfino, Claudia Casarsa and Gianni Sava.

Affiliation: Callerio Foundation Onlus, Via A. Fleming 22-31/b, 34127 Trieste.

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.

Keywords:

Cancer, Cell cycle, In vitro, Metastasis, Ruthenium, Treatment, signal transduction modulator, oral carcinoma, Ataxia telangiectasia-mutated protein kinase, phosphatases.



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Article Details

Volume: 12
Issue Number: 8
First Page: 949
Last Page: 958
Page Count: 10
DOI: 10.2174/187152012802650039
Price: $58
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