Bimodal effects of 1R,2R-diaminocyclohexane(trans-diacetato)(dichloro)platinum(IV) on cell cycle checkpoints.

Abstract

1R,2R-Diaminocyclohexane(trans-diacetato)(dichloro)-platinum(IV) (DACH-acetato-Pt) is a novel platinum-based agent that is highly effective against cisplatin-resistant ovarian tumor cells. To probe its cellular mechanism, the effects of DACH-acetato-Pt (0-6.4 microM) on cell cycle checkpoints were examined using the ovarian cancer A2780 cell line as the model system. We found that DACH-acetato-Pt at > or =0.2 microM dramatically inhibited cell growth and induced cell death. At concentrations < or =0.6 microM (low effective concentrations), DACH-acetato-Pt specifically induced G(1) phase arrest by selectively inhibiting cyclin-dependent kinase 4 (Cdk4) and Cdk2 activities. The Cdc2 activity, which regulates G(2)-M phase progression, was unaffected by the drug at these concentrations. At concentrations >0.6 microM (high effective concentrations), DACH-acetato-Pt first transiently inhibited S-phase progression and then blocked cell cycle progression at both G(1) and G(2) phases. These cell cycle effects were associated with sequential inhibitions of Cdk2/cyclin A activity, Cdk4 and Cdk2 activities, and Cdc2 kinase activity. Following the cell cycle effects, both the low and high effective concentrations of DACH-acetato-Pt induced cell death through apoptosis. These results indicate that DACH-acetato-Pt activates multiple cell cycle checkpoints in a bimodal manner and suggest that the cell cycle effects demonstrated in these studies may be linked to its ability to induce apoptosis.

• Authors: J Kuang, G He, Z Huang, A R Khokhar, Z H Siddik
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 7 Issue 11 Pg. 3629-39 (Nov 2001) ISSN: 1078-0432 [Print] United States
• PMID: 11705886 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• (diaminocyclohexane)(diacetato)(dichloro)platinum
• Antineoplastic Agents
• Organoplatinum Compounds
• Proto-Oncogene Proteins
• Protein Serine-Threonine Kinases
• CDC2 Protein Kinase
• CDC2-CDC28 Kinases
• CDK2 protein, human
• CDK4 protein, human
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinases
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• CDC2 Protein Kinase (drug effects, metabolism)
• CDC2-CDC28 Kinases
• Cell Count
• Cell Cycle (drug effects)
• Cell Death (drug effects)
• Cell Division (drug effects)
• Cisplatin (analogs & derivatives, pharmacology)
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinases (drug effects, metabolism)
• Dose-Response Relationship, Drug
• G1 Phase (drug effects)
• G2 Phase (drug effects)
• Humans
• In Situ Nick-End Labeling
• Kinetics
• Models, Biological
• Organoplatinum Compounds
• Protein Serine-Threonine Kinases (drug effects, metabolism)
• Proto-Oncogene Proteins
• Time Factors
• Tumor Cells, Cultured