PT  - JOURNAL ARTICLE
AU  - Stéphane Léonce
AU  - Valérie Pérez
AU  - Stéphanie Lambel
AU  - Delphine Peyroulan
AU  - François Tillequin
AU  - Sylvie Michel
AU  - Michel Koch
AU  - Bruno Pfeiffer
AU  - Ghanem Atassi
AU  - John A Hickman
AU  - Alain Pierré
TI  - Induction of Cyclin E and Inhibition of DNA Synthesis by the Novel Acronycine Derivative <a href="pending:yes" l:ref-type="genbank" l:ref="S23906">S23906</a>-1 Precede the Irreversible Arrest of Tumor Cells in S Phase Leading to Apoptosis
AID  - 10.1124/mol.60.6.1383
DP  - 2001 Dec 01
TA  - Molecular Pharmacology
PG  - 1383--1391
VI  - 60
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/60/6/1383.short
4100  - http://molpharm.aspetjournals.org/content/60/6/1383.full
SO  - Mol Pharmacol2001 Dec 01; 60
AB  - 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 thatS23906-1 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.