Visit our Expo - Redox and Inflammation signaling 2012

V. Phosphatases as key cell signaling intermediates Poster V, 2
Novel Cdc25 inhibitors: activity in MCF-7 cells and potentiation of cytotoxic drugs
Souhayla El Maâdidi, Laurent Brault and Denyse Bagrel
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, UFR SciFA,
Université Paul Verlaine-Metz, Campus Bridoux, rue du Général Delestraint, 57070
Metz, France. E-mail: bagrel@univ-metz.fr
The Cdc25s dual-specificity phosphatases are key regulators of cell cycle progression which
dephosphorylate and activate cycline dependent kinases. Three homologs of Cdc25
phosphatases exist in humans: Cdc25A, Cdc25B, and Cdc25C. Cdc25B and Cdc25C regulate
the G2/M cell cycle transition while Cdc25A is responsible for regulating the G1/S transition.
The overexpression of Cdc25A and B is frequently associated with a wide variety of cancers.
Taken into account there regulatory role, the aim of this study is a development of new Cdc25
inhibitors. In our laboratory, novel maleic anhydride derivatives have been synthetised
(named 6a to 6j) and tested in vitro using pNPP as substrate on the three recombinant GST-
Cdc25A, GST-Cdc25B and GST-Cdc25C . These inhibitors differ in the size of their fatty
acid chain, the most active of them having the longest chain. The in vitro inhibitory activity
was confirmed by testing those compounds on two breast cancer cell lines: MCF-7 and its
counterpart resistant to vincristine Vcr-R. Four compounds were chosen: 6a presenting the
shortest fatty acid chain (6 carbons) and inactive in vitro, 6e having a mid-long chain (11
carbons) showing an intermediate activity, and the 2 most potent inhibitors in vitro (6i and 6j)
with the longest side chain (17 carbons). These two compounds induced a cell cycle blockage
in G0/G1 phase and a decrease of cell proportions in S and G2/M phases after 24 and 48h
treatments. Moreover, apoptosis was triggered within 48h-treatment, without oxidative burst.
We also showed that 6i and 6j are able to potentiate the effects of cisplatin and adriamycin, at
least by an additional effect. Thus, we can conclude that maleic anhydride-derivatives may
mediate apoptosis through a cell cycle blockage via inhibition of the phosphatases Cdc25 and
may present a potential interest in therapeutic strategies against cancer.
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