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Bimodal Effects of 1R,2R-Diaminocyclohexane(trans-diacetato)(dichloro)platinum(IV) on Cell Cycle Checkpoints¹

Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009

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 µM) on cell cycle checkpoints were examined using the ovarian cancer A2780 cell line as the model system. We found that DACH-acetato-Pt at 0.2 µM dramatically inhibited cell growth and induced cell death. At concentrations 0.6 µM (low effective concentrations), DACH-acetato-Pt specifically induced G₁ phase arrest by selectively inhibiting cyclin-dependent kinase 4 (Cdk4) and Cdk2 activities. The Cdc2 activity, which regulates G₂-M phase progression, was unaffected by the drug at these concentrations. At concentrations >0.6 µM (high effective concentrations), DACH-acetato-Pt first transiently inhibited S-phase progression and then blocked cell cycle progression at both G₁ and G₂ 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.