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Vol. 60, Issue 6, 1383-1391, December 2001

Induction of Cyclin E and Inhibition of DNA Synthesis by the Novel Acronycine Derivative S23906-1 Precede the Irreversible Arrest of Tumor Cells in S Phase Leading to Apoptosis

Stéphane Léonce, Valérie Pérez, Stéphanie Lambel, Delphine Peyroulan, François Tillequin, Sylvie Michel, Michel Koch, Bruno Pfeiffer, Ghanem Atassi, John A Hickman, and Alain Pierré

Institut de Recherches Servier, Suresnes, France (S.L., V.P., S.L., D.P., G.A., J.A.H., A.P.); Laboratoire de Pharmacognosie de l'Université René Descartes, Paris, France (F.T., S.M., M.K.); ADIR et Cie, Courbevoie, France (B.P.)

S23906-1 is a diester derivative of 1,2-dihydrobenzo[b]acronycine with an unknown mechanism of action. This cytotoxic compound was 20-fold more potent than acronycine in inhibiting the proliferation of six tumor cell lines. Using a clonogenic assay of cell survival, the HT29 human colon carcinoma cell line was 100-fold more sensitive to S23906-1 than acronycine. Cell cycle analysis, by flow cytometry, showed that S23906-1 induced a partially reversible arrest of HT29 cells in G2+M at 1 µM and below and an irreversible arrest in S phase at 2.5 µM and above. These cell cycle effects were followed by cell death through apoptosis, quantified by annexin-V labeling. Inhibition of DNA synthesis was observed by complete prevention of bromodeoxyuridine (BrdU) incorporation after only 4 h of incubation with 5 µM S23906-1. Interestingly, under the same experimental conditions, a significant increase of cyclin E protein level was observed without any modification of cyclins D1, D2, D3, or A. This overexpressed cyclin E protein was not complexed with Cdk2, as shown by western blotting for Cdk2 in immunoprecipitates of cyclin E. Similar inhibition of BrdU incorporation and elevation of cyclin E protein were observed after treatment with cytosine arabinoside, which reversibly inhibited progression into S phase, but not after DNA damage induced by cisplatin. S23906-1 thus has a novel mechanism of action. A cell line resistant to S23906-1 showed that overexpression of cyclin E was implicated in the novel cytotoxic activity of this compound.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics