Inhibition of human tumor cell growth in vivo by an orally bioavailable inhibitor of CDC25 phosphatases
- Marie-Christine Brezak1,
- Muriel Quaranta2,
- Marie-Odile Contour-Galcera1,
- Olivier Lavergne1,
- Odile Mondesert2,
- Pierrïck Auvray3,
- Philip G. Kasprzyk4,
- Gregoire P. Prevost1 and
- Bernard Ducommun2
- 1IPSEN, Institut Henri Beaufour, Les Ulis, France; 2Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération-Centre National de la Recherche Scientifique, UMR5088-IFR109 “Institut d'Exploration Fonctionnelle des Génomes,” Université Paul Sabatier, Toulouse, France; 3Cellis Pharma, Saint Malo, France; and 4IPSEN, Biomeasure, Milford, Massachusetts
- Requests for reprints: Bernard Ducommun, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération-Centre National de la Recherche Scientifique, UMR5088, 118 route de Narbonne 4R3B1, 31062 Toulouse, France. Phone: 33-5-6155-8110; Fax: 33-5-6155-8109. E-mail: ducommun{at}cict.fr
Abstract
Cell cycle regulators, such as the CDC25 phosphatases, are potential targets for the development of new anticancer drugs. Here we report the identification and the characterization of BN82685, a quinone-based CDC25 inhibitor that is active in vitro and in vivo. BN82685 inhibits recombinant CDC25A, B, and C phosphatases in vitro. It inhibits the growth of human tumor cell lines with an IC50 in the submicromolar range, independently of their resistance to chemotherapeutic agents. This inhibitory effect is irreversible on both the purified CDC25 enzyme in vitro and on tumor cell proliferation. The specificity of BN82685 towards the CDC25 phosphatases is shown by an increase in cyclin-dependent kinase 1 tyrosine 15 phosphorylation, by the reversion of the mitosis-inducing effect of CDC25B overexpression in HeLa cells, and by the lack of a growth inhibitory effect in an assay based on the use of a CDC25-independent fission yeast model. Finally, when administered p.o., BN82685 is shown to inhibit the growth of the human pancreatic tumor Mia PaCa-2 xenografted in athymic nude mice. BN82685 is therefore a promising new compound targeting CDC25, which confirms the interest of the inhibition of these enzymes as an anticancer therapeutic strategy.
Footnotes
-
Grant support: Centre National de la Recherche Scientifique, l'Université Paul Sabatier, and la Ligue Nationale Contre le Cancer (Equipe Labellisée).
-
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
Note: M-C. Brezak and M. Quaranta contributed equally to this work.
-
- Accepted July 15, 2005.
- Received May 23, 2005.
- Revision received June 25, 2005.
- American Association for Cancer Research
