Roscovitine (ROSC), a selective blocker of cyclin-dependent kinases (CDKs) efficiently inhibits proliferation of exponentially growing human MCF-7 breast cancer cells by induction of cell cycle arrest and p53-mediated apoptosis. ROSC blocks MCF-7 cells in G(2) phase in a time- and concentration-dependent manner. However, ROSC exerts a much weaker antiproliferative effect on human diploid fibroblasts. Therefore, in this study we questioned whether and to what extent the antiproliferative effect of ROSC depends on the cell cycle status of cancer cells exposed to the drug. We investigated the action of ROSC on asynchronous, exponentially growing, and on synchronized human MCF-7 breast cancer cells. MCF-7 cells were arrested in G(1) phase after serum withdrawal and in S phase by hydroxyurea. After serum refeeding, synchronized cells started to reenter the active cell cycle after 12 h. Exposure of G(1)-synchronized cells to ROSC prolonged the cell cycle arrest and was accompanied by a decrease in S-phase cells after 24 h. A similar but weaker trend occurred after ROSC administration, to cells released from G(1) arrest for 4 h. ROSC diminished the frequency of S-phase cells. Exposure of MCF-7 cells released from G(1) arrest to ROSC for 24 h resulted in an increase of the G(1)-cell population by 20%. Exposure to ROSC of MCF-7 cells released from S-phase block increased the ratio of S-phase cells. These results indicate that the cell cycle status of cancer cells prior to the onset of therapy determines the outcome of treatment.
Antineoplastic Agents Breast Neoplasms