Bimodal effects of 1R,2R-diaminocyclohexane(trans-diacetato)(dichloro)platinum(IV) on cell cycle checkpoints.
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.
Kuang
J
J
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.
He
G
G
Huang
Z
Z
Khokhar
A R
AR
Siddik
Z H
ZH
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000187:drug effects / Q000378:metabolism; D042846:CDC2-CDC28 Kinases; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D007700:Kinetics; D008954:Models, Biological; D009944:Organoplatinum Compounds; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D013997:Time Factors; D014407:Tumor Cells, Cultured
C119451:(diaminocyclohexane)(diacetato)(dichloro)platinum; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D002945:Cisplatin